This report provides an updated classification of inborn errors of immunity (IEIs) involving 508 different genes and 17 phenocopies. Of these, we report 67 novel monogenic defects and 2 phenocopies due to neutralizing anti-cytokine autoantibodies or somatic mutations, which either have been discovered since the previous update (published June 2022) or were reported earlier but have been recently confirmed and/or expanded. The new additions were made after rigorous review of new genetic descriptions of IEIs by the International Union of Immunological Societies (IUIS) Expert Committee using criteria established to define IEI. Although similar pathogenic variants in one gene, in terms of both classes of mutation (missense, nonsense, etc.) and impact on protein function, can result in a spectrum of phenotypic manifestations, they are herein classified according to the most consistently reported phenotype. In addition, because different variants in a single gene can result in recognizable diseases due to gain or loss of function, such cases are classified according to their clinical manifestations as a distinct entry in the same or a different table depending on the associated phenotype. This report will serve as a valuable resource for clinical immunologists and geneticists involved in the molecular diagnosis of individuals with heritable and acquired immunological disorders. Moreover, we expect this report to also serve as a valuable resource for all disciplines of medicine, since patients with IEIs may be first seen by rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, and pulmonologists, depending upon their spectrum of presenting clinical features. Finally, expanding the known monogenic and related causes of human immune diseases requires dissection of underlying cellular and molecular mechanisms, which reveals fundamental requirements for specific genes, pathways, processes, and even cell types. Such knowledge may not only contribute to improved patient diagnosis and management but also pave the way to the development and implementation of therapies that target the cause—rather than the symptoms—of these conditions.

Subjects:
Clinical phenotypes, Inborn errors of immunity, Infections and auto-antibodies, Phenocopies of inborn errors

Inborn errors of immunity (IEIs) are, by definition, caused by damaging germline variants in single genes. IEIs present clinically as increased susceptibility to infections, autoimmunity, autoinflammation, allergy, bone marrow failure, and/or malignancy. Although individual IEIs are rare, collectively IEIs are not, and they represent a significant health burden (1). Indeed, a recent study reported that the incidence of IEIs in the USA was 6 per 10,000 people (2). Genetic variants underlie IEI by altering the encoded gene product, such as abolition (null) or reduction (hypomorphic) of protein expression, titration of the intrinsic function of the protein (gain of function [GOF] or loss of function [LOF]), or acquiring novel functions (neomorphic) (3, 4). Mechanisms of disease in IEIs depend on the nature of the variant and mode of inheritance. Thus, monoallelic variants can cause disease by haploinsufficiency, negative dominance, or GOF. In contrast, biallelic genetic lesions (homozygous, compound heterozygous) cause autosomal recessive (AR) traits by loss of expression, LOF, GOF, or neomorphic function of the encoded protein. X-linked recessive traits arise from LOF or GOF variants on the X chromosome, either in hemizygosity in males or in a homozygous state in females.

The careful genetic dissection and functional study of individual IEIs has aided in confirming or contrasting the knowledge obtained from mouse models or has offered novel insights on protein function within different immune pathways and specific immune cells (5, 6). Thus, by linking defined monogenic defects with clinical phenotypes of immune dysregulation, IEIs represent elegant models of the human immune system and have thus been referred to as “experiments of nature” (7). IEIs have also revealed mechanisms of disease pathogenesis and enabled the implementation of gene- or pathway-specific therapies for the treatment of rare and common conditions and established fundamental aspects of human immunology (8, 9, 10). Thus, the study of IEIs has driven profound advances in molecular medicine and human biology.

Since 1970, an international expert committee comprising pediatric and adult clinical immunologists, clinician/scientists, and researchers in basic immunology—initially under the auspices of the World Health Organization and currently the International Union of Immunological Societies (IUIS)—has provided the clinical and research communities with an update of genetic causes of immune deficiency and dysregulation (https://iuis.org/committees/iei/).

IEIs are currently categorized into 10 tables, with subtables segregating groups of disorders into overlapping phenotypes. These tables describe combined immunodeficiencies (Table 1; 3 subtables); combined immunodeficiencies with syndromic features (Table 2; 9 subtables); predominantly antibody deficiencies (Table 3; 3 subtables); diseases of immune dysregulation (Table 4; 7 subtables); congenital defects of phagocytes (Table 5; 4 subtables); defects in intrinsic and innate immunity (Table 6; 9 subtables); autoinflammatory diseases (Table 7; 3 subtables); complement deficiencies (Table 8); bone marrow failure (Table 9); and phenocopies of IEIs (Table 10) (Fig. 1, A and B) (4).

Table 1.

Immunodeficiencies affecting cellular and humoral immunity

DiseaseGenetic defectInheritanceOMIMT cellsB cellsIgAssociated features
1. T-B+ severe combined immune deficiency (SCID) 
γc deficiency (common gamma chain SCID, CD132 deficiency) IL2RG XL 300400 Very low Normal to high Low Low NK 
JAK3 deficiency JAK3 AR 600802 Very low Normal to high Low Low NK 
IL-7Rα deficiency IL7R AR 608971 Very low Normal to high Low Normal NK 
CD45 deficiency PTPRC AR 619924 Very low Normal Low Normal γ/δ T cells 
CD3δ deficiency CD3D AR 615617 Very low Normal Low Normal NK, no γ/δ T cells 
CD3ε deficiency CD3E AR 615615 Very low Normal Low Normal NK, no γ/δ T cells 
CD3ζ deficiency CD247 AR 610163 Very low Normal Low Normal NK, no γ/δ T cells 
Coronin-1A deficiency CORO1A AR 615401 Very low Normal Low Detectable thymus 
LAT deficiency LAT AR 617514 Normal to low Normal to low High Typical SCID or CID, the latter with adenopathy, splenomegaly, recurrent infections, autoimmunity 
SLP76 deficiency LCP2 AR 619374 Reduced Normal High IgM, low IgA Early-onset skin abscesses, rash, recurrent infections, autoimmunity 
2. T-B-SCID 
RAG deficiency RAG1 AR 179615 Very low Very low Decreased Normal NK cell number, but increased risk of graft rejection, possibly due to activated NK cells 
RAG2 179616 
DCLRE1C (Artemis) deficiency DCLRE1C AR 602450 Very low Very low Decreased Normal NK cell number, but increased risk of graft rejection, possibly due to activated NK cells, radiation sensitivity 
DNA-PKcs deficiency PRKDC AR 615966 Very low Very low Variable Normal NK, radiation sensitivity, microcephaly 
Cernunnos/XLF deficiency NHEJ1 AR 611291 Very low Very low Decreased Normal NK, radiation sensitivity, microcephaly 
DNA ligase IV deficiency LIG4 AR 606593 Very low Very low Decreased Normal NK, radiation sensitivity, microcephaly 
ADA deficiency ADA AR 102700 Very low Low, decreasing Low, decreasing Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects, sensorineural deafness, and multicentric dermatofibrosarcoma protuberans 
AK2 defect AK2 AR 267500 Very low Very low Decreased Reticular dysgenesis with neutropenia; deafness 
Activated RAC2 defect RAC2 AD GOF 618986 Very low Very low Low, poor specific antibody responses Recurrent bacterial and viral infections, lymphoproliferation; neutropenia 
NUDCD3 deficiency NUDCD3 AR NA Very low Very low Decreased OS, abnormal VDJ recombination 
3. Combined immunodeficiency (CID), generally less profound than SCID 
CD40 ligand (CD154) deficiency CD40LG XL 308230 Normal to low sIgM+IgD+ naïve B cells present; IgG+, IgA+, IgE+ memory B cells absent IgM normal or high, other Ig isotypes low Severe and opportunistic infections, idiopathic neutropenia; hepatitis and cholangitis, Cryptosporidium infections, cholangiocarcinoma; neutropenia and other blood cytopenias; peripheral neuroectodermal tumors 
CD40 deficiency CD40 AR 606843 Normal Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections 
ICOS deficiency ICOS AR 607594 Normal Normal Low Recurrent infections, autoimmunity, gastroenteritis, granulomas 
ICOSL deficiency ICOSLG AR 620825 Low Low Low Recurrent bacterial and viral infections, neutropenia 
CD3γ deficiency CD3G AR 615607 Normal number, but low TCR expression Normal Normal Immune deficiency and autoimmunity of variable severity 
CD8 deficiency CD8A AR 608957 Absent CD8, normal CD4 Normal Normal Recurrent infections, may be asymptomatic 
ZAP-70 deficiency (ZAP70 LOF) ZAP70 AR 269840 Low CD8 number, normal CD4 number but with poor function Normal Normal May have immune dysregulation, autoimmunity 
ZAP-70 combined hypomorphic and activating mutations ZAP70 AR (LOF/GOF) 617006 Decreased CD8, normal or decreased CD4 cells Normal or decreased Normal IgA, low IgM, low/normal IgG; protective Ab responses to vaccines Severe autoimmunity (bullous pemphigoid, inflammatory colitis) 
MHC class I deficiency TAP1 AR 604571 Low CD8, normal CD4, absent MHC I on lymphocytes Normal Normal Vasculitis, pyoderma gangrenosum 
TAP2 AR 620813 
TAPBP AR 620814 
B2M AR 241600 Sinopulmonary infections, cutaneous granulomas. Absent β2m-associated proteins MHC I, CD1a, CD1b, and CD1c 
MHC class II deficiency group A, B, C, D CIITA AR 209920 Low CD4+ T cells, reduced MHC II expression on lymphocytes Normal Normal to low Failure to thrive, respiratory and gastrointestinal infections, liver/biliary tract disease 
RFXANK AR 620815 
RFX5 AR 620816 
RFXAP AR 620817 
IKAROS deficiency IKZF1 AD DN 616873 No memory T cells No memory B cells Low Ig Recurrent sinopulmonary infections, PJP, and early-onset CID 
DOCK8 deficiency DOCK8 AR 243700 T-cell lymphopenia, reduced naïve CD8 T cells, increased exhausted CD8+ TEM cells, reduced MAIT, NKT cells, increased γδ cells; poor proliferation; few Treg with poor function Increased total B cells, reduced memory B cells, poor peripheral B-cell tolerance Low IgM, normal/high IgG and IgA, very high IgE, poor antibody responses Low NK cells with poor function. Eosinophilia, recurrent infections, cutaneous viral, fungal, and staphylococcal infections, severe atopy/allergic disease, cancer diathesis 
DOCK2 deficiency DOCK2 AR 616433 Low Normal IgG normal or low, poor antibody responses Early invasive herpes viral, bacterial infections, normal NK cell number, but defective function. Poor interferon responses in hematopoietic and nonhematopoietic cells 
Polymerase δ deficiency POLD1 AR 620836 Low CD4 T cells Low B cells but normal maturation Low IgG Recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability 
POLD2 600815 
POLD3 AR 620869 Low naïve CD4 T cells Normal Low IgG and IgA, normal IgM, high IgE Recurrent infections and OS 
PRIM1 PRIM1 AR 620005 Normal Low B cells Low or absent immunoglobulins Prominent forehead, microcephaly, triangular face, hypertelorism, small low-set ears, flat nasal bridge, straight horizontal and bilateral cryptorchidism. Hepatic fibrosis, variable basal ganglia calcification. Growth failure. Recurrent pneumonias, GI and systemic infections. ↑ type I interferon signature 
RHOH deficiency RHOH AR 618307 Normal, few naïve T cells, restricted repertoire, poor proliferation to CD3 Normal Normal HPV infection, lung granulomas, molluscum contagiosum, lymphoma 
STK4 deficiency STK4 AR 614868 CD4 lymphopenia, reduced naïve T cells, increased TEM and TEMRA cells, poor proliferation Reduced memory B cells Reduced IgM, increased IgG, IgA, IgE, impaired Ab responses Intermittent neutropenia, bacterial, viral (HPV, EBV, molluscum), candidal infections, lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease 
TCRα deficiency TRAC AR 615387 Absent TCRαβ except for a minor CD3-dim TCRαβ population; most T cells γδ; poor proliferation Normal Normal Recurrent viral, bacterial, fungal infections, immune dysregulation and autoimmunity, diarrhea 
LCK deficiency LCK AR 615758 Low CD4+, low Treg, restricted T-cell repertoire, poor TCR signaling Normal Normal IgG and IgA, high IgM Recurrent infections, immune dysregulation, autoimmunity 
ITK deficiency ITK AR 613011 Progressive CD4 T-cell lymphopenia; reduced T-cell activation Normal Normal to low serum Ig EBV-associated B-cell lymphoproliferation, lymphoma, immune dysregulation 
MALT1 deficiency MALT1 AR 615468 Normal number, poor proliferation Normal Normal levels, poor specific antibody response Bacterial, fungal, and viral infections 
CARD11 deficiency CARD11 AR LOF 615206 Normal number, predominantly naïve T cells, poor proliferation Normal, transitional B-cell predominance Absent/low PJP, bacterial and viral infections 
BCL10 deficiency BCL10 AR 616098 Normal number, few memory T and Treg cells, poor antigen and anti-CD3 proliferation Normal number, decreased memory and switched B cells Low Recurrent bacterial and viral infections, candidiasis, gastroenteritis 
IL-21 deficiency IL21 AR 615767 Normal number, normal/low function Low, decreased memory and switched B cells Hypogammaglobulinemia, poor specific antibody responses, increased IgE Severe early-onset colitis, recurrent sinopulmonary infections 
IL-21R deficiency IL21R AR 615207 Normal number, low cytokine production, poor antigen proliferation Normal, decreased memory and switched B cells Recurrent infections, P. jirovecii, Cryptosporidium infections, liver disease 
OX40 deficiency TNFRSF4 AR 615593 Normal numbers, low antigen-specific memory CD4+ Normal numbers, low memory B cells Normal Impaired immunity to HHV8, Kaposi’s sarcoma 
IKBKB deficiency IKBKB AR 615592 Normal number, absent Treg and γ/δ T cells, impaired TCR activation Normal number, poor function Low Recurrent bacterial, viral, fungal infections, opportunistic infections 
NIK deficiency MAP3K14 AR 620449 Normal number, poor proliferation to antigen Low, low switched memory B cells Low Ig’s Low NK number and function, recurrent bacterial, viral, and Cryptosporidium infections 
RelB deficiency RELB AR 617585 Normal number, poor diversity, reduced proliferation to mitogens, no response to Ag Marked increase in B-cell number Normal Ig levels but impaired specific antibody responses Recurrent infections 
Moesin deficiency MSN XL 300988 Low number may improve over time, defective migration and proliferation Low number Low Ig’s over time Recurrent infections with bacteria, varicella, neutropenia 
TFRC deficiency TFRC AR 616740 Normal number, poor proliferation Normal number, low memory B cells Low Recurrent infections, neutropenia, thrombocytopenia 
c-Rel deficiency REL AR 619652 Normal, decreased memory CD4, poor proliferation Low, mostly naïve, few switched memory B cells, impaired proliferation Low, poor specific antibody responses Recurrent infections with bacteria, mycobacteria, Salmonella, and opportunistic organisms. Defective innate immunity 
FCHO1 deficiency FCHO1 AR 619164 Low, poor proliferation Normal number Normal Recurrent infections (viral, mycobacterial, bacterial, fungal), lymphoproliferation, failure to thrive, increased activation-induced T-cell death, defective clathrin-mediated endocytosis 
PAX1 deficiency PAX1 AR 615560 Severe T-cell lymphopenia, low TRECs Normal number Normal Omenn-like syndrome (erythroderma, lymphocytosis, eosinophilia, severe/recurrent infections), no thymus, T-cell deficiency not corrected by HSCT. Otofaciocervical syndrome type 2, ear abnormalities 
ITPKB deficiency ITPKB AR NA Very few T cells Normal Normal IgM, IgA; low IgG FTT, recurrent bacterial/fungal infections, pan-leukopenia, anemia, thrombocytopenia 
SASH3 deficiency SASH3 XL 301082 T/NK cell lymphopenia B-cell lymphopenia Low, poor specific antibody responses Recurrent sinopulmonary, cutaneous and mucosal infections, refractory autoimmune cytopenia/neutropenia 
MAN2B2 deficiency MAN2B2 AR NA Low T cells Low B cells Normal/low Recurrent infections, vasculitis, arthritis, FTT, microcephaly, neurodevelopmental delay, congenital disorder of glycosylation 
COPG1 deficiency COPG1 AR 620983 T-cell lymphopenia Normal Normal but poor Ig response to vaccines Recurrent pneumonia, viral respiratory infections, chronic EBV, CMV viremia, FTT, bronchiectasis 
HELIOS deficiency IKZF2 AD
AR 		NA Increased activated T cells Normal number, reduced memory Reduced Recurrent upper respiratory infections/pneumonia, thrush, mucosal ulcers, chronic lymphadenopathy, SLE, ITP, AIHA (Evans syndrome), EBV-associated HLH, lymphoma 
IKKα deficiency CHUK AR NA Normal Reduced Low Recurrent bacterial, viral, fungal infections, absent secondary lymphoid tissues; skeletal abnormalities, FTT 
IRF4 multimorphic (IRF4 R95T) IRF4 AD-neomorph NA Normal counts of circulating T cells; normal proportions of naïve, CM, EM, and TEMRA CD4+T cells, reduced TCM, TEM, TEMRACD8+T-cell proportions; low TH17 and TFHcells Reduced CD19+cells; increased naïve B cells; reduced class-switched memory B cells; decreased plasmablasts and plasma cells Agammaglobulinemia or extremely low IgM, IgG, and IgA serum levels Early-onset recurrent sinopulmonary infections with P. jirovecii, pneumonia, severe viral disease (CMV and EBV), localized disease with weakly virulent (BCG vaccine) or pathogenic mycobacteria (Mycobacterium bovis), and chronic diarrhea 
Primary antibody deficiency/CID due to IRF4 variants IRF4 AD-neomorph NA Lymphocytes, low naïve CD4 and CD8 T cell counts, and high terminal effector CD4 and CD8 T cell counts   Hypogammaglobulinemia, low IgM, IgG, and IgA serum levels, early gray hairing 
NFATC1 deficiency NFATC1 AR NA Normal/increased proportions of CD8+T, lower proportions of naïve and TCMCD4+and CD8+T cells, increased TCMcells; lower proportions of Treg, TFH, TH1, TH2 Normal, low proportions of switched memory/increased proportions of naïve B cells Hypogammaglobulinemia, decreased or normal serum IgA, decreased serum IgG and IgM, low titers to pneumococcus and HBV vaccines Early-onset sinopulmonary infections with bronchiectasis. May present with recurrent warts, bacterial skin infections (folliculitis and abscesses). Scoliosis in 2 of 3 patients 
FOXI3 haploinsufficiency FOXI3 AD NA CD4 and CD8 T-cell lymphopenia Slightly decreased Normal Abnormal TRECS, thymus hypoplasia; increased head circumference 
PSMB10-associated OS PSMB10 p.Asp56His/p.Gly201Arg AD 620807 Low, skewed TCR repertoire. Low TRECs Low or absent Low OS (diarrhea, alopecia, rash). Severe and recurrent infections (candidiasis, disseminated VZV and CMV, pneumocystis pneumonia, skin infections).
Hypereosinophilia 
DiseaseGenetic defectInheritanceOMIMT cellsB cellsIgAssociated features
1. T-B+ severe combined immune deficiency (SCID) 
γc deficiency (common gamma chain SCID, CD132 deficiency) IL2RG XL 300400 Very low Normal to high Low Low NK 
JAK3 deficiency JAK3 AR 600802 Very low Normal to high Low Low NK 
IL-7Rα deficiency IL7R AR 608971 Very low Normal to high Low Normal NK 
CD45 deficiency PTPRC AR 619924 Very low Normal Low Normal γ/δ T cells 
CD3δ deficiency CD3D AR 615617 Very low Normal Low Normal NK, no γ/δ T cells 
CD3ε deficiency CD3E AR 615615 Very low Normal Low Normal NK, no γ/δ T cells 
CD3ζ deficiency CD247 AR 610163 Very low Normal Low Normal NK, no γ/δ T cells 
Coronin-1A deficiency CORO1A AR 615401 Very low Normal Low Detectable thymus 
LAT deficiency LAT AR 617514 Normal to low Normal to low High Typical SCID or CID, the latter with adenopathy, splenomegaly, recurrent infections, autoimmunity 
SLP76 deficiency LCP2 AR 619374 Reduced Normal High IgM, low IgA Early-onset skin abscesses, rash, recurrent infections, autoimmunity 
2. T-B-SCID 
RAG deficiency RAG1 AR 179615 Very low Very low Decreased Normal NK cell number, but increased risk of graft rejection, possibly due to activated NK cells 
RAG2 179616 
DCLRE1C (Artemis) deficiency DCLRE1C AR 602450 Very low Very low Decreased Normal NK cell number, but increased risk of graft rejection, possibly due to activated NK cells, radiation sensitivity 
DNA-PKcs deficiency PRKDC AR 615966 Very low Very low Variable Normal NK, radiation sensitivity, microcephaly 
Cernunnos/XLF deficiency NHEJ1 AR 611291 Very low Very low Decreased Normal NK, radiation sensitivity, microcephaly 
DNA ligase IV deficiency LIG4 AR 606593 Very low Very low Decreased Normal NK, radiation sensitivity, microcephaly 
ADA deficiency ADA AR 102700 Very low Low, decreasing Low, decreasing Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects, sensorineural deafness, and multicentric dermatofibrosarcoma protuberans 
AK2 defect AK2 AR 267500 Very low Very low Decreased Reticular dysgenesis with neutropenia; deafness 
Activated RAC2 defect RAC2 AD GOF 618986 Very low Very low Low, poor specific antibody responses Recurrent bacterial and viral infections, lymphoproliferation; neutropenia 
NUDCD3 deficiency NUDCD3 AR NA Very low Very low Decreased OS, abnormal VDJ recombination 
3. Combined immunodeficiency (CID), generally less profound than SCID 
CD40 ligand (CD154) deficiency CD40LG XL 308230 Normal to low sIgM+IgD+ naïve B cells present; IgG+, IgA+, IgE+ memory B cells absent IgM normal or high, other Ig isotypes low Severe and opportunistic infections, idiopathic neutropenia; hepatitis and cholangitis, Cryptosporidium infections, cholangiocarcinoma; neutropenia and other blood cytopenias; peripheral neuroectodermal tumors 
CD40 deficiency CD40 AR 606843 Normal Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections 
ICOS deficiency ICOS AR 607594 Normal Normal Low Recurrent infections, autoimmunity, gastroenteritis, granulomas 
ICOSL deficiency ICOSLG AR 620825 Low Low Low Recurrent bacterial and viral infections, neutropenia 
CD3γ deficiency CD3G AR 615607 Normal number, but low TCR expression Normal Normal Immune deficiency and autoimmunity of variable severity 
CD8 deficiency CD8A AR 608957 Absent CD8, normal CD4 Normal Normal Recurrent infections, may be asymptomatic 
ZAP-70 deficiency (ZAP70 LOF) ZAP70 AR 269840 Low CD8 number, normal CD4 number but with poor function Normal Normal May have immune dysregulation, autoimmunity 
ZAP-70 combined hypomorphic and activating mutations ZAP70 AR (LOF/GOF) 617006 Decreased CD8, normal or decreased CD4 cells Normal or decreased Normal IgA, low IgM, low/normal IgG; protective Ab responses to vaccines Severe autoimmunity (bullous pemphigoid, inflammatory colitis) 
MHC class I deficiency TAP1 AR 604571 Low CD8, normal CD4, absent MHC I on lymphocytes Normal Normal Vasculitis, pyoderma gangrenosum 
TAP2 AR 620813 
TAPBP AR 620814 
B2M AR 241600 Sinopulmonary infections, cutaneous granulomas. Absent β2m-associated proteins MHC I, CD1a, CD1b, and CD1c 
MHC class II deficiency group A, B, C, D CIITA AR 209920 Low CD4+ T cells, reduced MHC II expression on lymphocytes Normal Normal to low Failure to thrive, respiratory and gastrointestinal infections, liver/biliary tract disease 
RFXANK AR 620815 
RFX5 AR 620816 
RFXAP AR 620817 
IKAROS deficiency IKZF1 AD DN 616873 No memory T cells No memory B cells Low Ig Recurrent sinopulmonary infections, PJP, and early-onset CID 
DOCK8 deficiency DOCK8 AR 243700 T-cell lymphopenia, reduced naïve CD8 T cells, increased exhausted CD8+ TEM cells, reduced MAIT, NKT cells, increased γδ cells; poor proliferation; few Treg with poor function Increased total B cells, reduced memory B cells, poor peripheral B-cell tolerance Low IgM, normal/high IgG and IgA, very high IgE, poor antibody responses Low NK cells with poor function. Eosinophilia, recurrent infections, cutaneous viral, fungal, and staphylococcal infections, severe atopy/allergic disease, cancer diathesis 
DOCK2 deficiency DOCK2 AR 616433 Low Normal IgG normal or low, poor antibody responses Early invasive herpes viral, bacterial infections, normal NK cell number, but defective function. Poor interferon responses in hematopoietic and nonhematopoietic cells 
Polymerase δ deficiency POLD1 AR 620836 Low CD4 T cells Low B cells but normal maturation Low IgG Recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability 
POLD2 600815 
POLD3 AR 620869 Low naïve CD4 T cells Normal Low IgG and IgA, normal IgM, high IgE Recurrent infections and OS 
PRIM1 PRIM1 AR 620005 Normal Low B cells Low or absent immunoglobulins Prominent forehead, microcephaly, triangular face, hypertelorism, small low-set ears, flat nasal bridge, straight horizontal and bilateral cryptorchidism. Hepatic fibrosis, variable basal ganglia calcification. Growth failure. Recurrent pneumonias, GI and systemic infections. ↑ type I interferon signature 
RHOH deficiency RHOH AR 618307 Normal, few naïve T cells, restricted repertoire, poor proliferation to CD3 Normal Normal HPV infection, lung granulomas, molluscum contagiosum, lymphoma 
STK4 deficiency STK4 AR 614868 CD4 lymphopenia, reduced naïve T cells, increased TEM and TEMRA cells, poor proliferation Reduced memory B cells Reduced IgM, increased IgG, IgA, IgE, impaired Ab responses Intermittent neutropenia, bacterial, viral (HPV, EBV, molluscum), candidal infections, lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease 
TCRα deficiency TRAC AR 615387 Absent TCRαβ except for a minor CD3-dim TCRαβ population; most T cells γδ; poor proliferation Normal Normal Recurrent viral, bacterial, fungal infections, immune dysregulation and autoimmunity, diarrhea 
LCK deficiency LCK AR 615758 Low CD4+, low Treg, restricted T-cell repertoire, poor TCR signaling Normal Normal IgG and IgA, high IgM Recurrent infections, immune dysregulation, autoimmunity 
ITK deficiency ITK AR 613011 Progressive CD4 T-cell lymphopenia; reduced T-cell activation Normal Normal to low serum Ig EBV-associated B-cell lymphoproliferation, lymphoma, immune dysregulation 
MALT1 deficiency MALT1 AR 615468 Normal number, poor proliferation Normal Normal levels, poor specific antibody response Bacterial, fungal, and viral infections 
CARD11 deficiency CARD11 AR LOF 615206 Normal number, predominantly naïve T cells, poor proliferation Normal, transitional B-cell predominance Absent/low PJP, bacterial and viral infections 
BCL10 deficiency BCL10 AR 616098 Normal number, few memory T and Treg cells, poor antigen and anti-CD3 proliferation Normal number, decreased memory and switched B cells Low Recurrent bacterial and viral infections, candidiasis, gastroenteritis 
IL-21 deficiency IL21 AR 615767 Normal number, normal/low function Low, decreased memory and switched B cells Hypogammaglobulinemia, poor specific antibody responses, increased IgE Severe early-onset colitis, recurrent sinopulmonary infections 
IL-21R deficiency IL21R AR 615207 Normal number, low cytokine production, poor antigen proliferation Normal, decreased memory and switched B cells Recurrent infections, P. jirovecii, Cryptosporidium infections, liver disease 
OX40 deficiency TNFRSF4 AR 615593 Normal numbers, low antigen-specific memory CD4+ Normal numbers, low memory B cells Normal Impaired immunity to HHV8, Kaposi’s sarcoma 
IKBKB deficiency IKBKB AR 615592 Normal number, absent Treg and γ/δ T cells, impaired TCR activation Normal number, poor function Low Recurrent bacterial, viral, fungal infections, opportunistic infections 
NIK deficiency MAP3K14 AR 620449 Normal number, poor proliferation to antigen Low, low switched memory B cells Low Ig’s Low NK number and function, recurrent bacterial, viral, and Cryptosporidium infections 
RelB deficiency RELB AR 617585 Normal number, poor diversity, reduced proliferation to mitogens, no response to Ag Marked increase in B-cell number Normal Ig levels but impaired specific antibody responses Recurrent infections 
Moesin deficiency MSN XL 300988 Low number may improve over time, defective migration and proliferation Low number Low Ig’s over time Recurrent infections with bacteria, varicella, neutropenia 
TFRC deficiency TFRC AR 616740 Normal number, poor proliferation Normal number, low memory B cells Low Recurrent infections, neutropenia, thrombocytopenia 
c-Rel deficiency REL AR 619652 Normal, decreased memory CD4, poor proliferation Low, mostly naïve, few switched memory B cells, impaired proliferation Low, poor specific antibody responses Recurrent infections with bacteria, mycobacteria, Salmonella, and opportunistic organisms. Defective innate immunity 
FCHO1 deficiency FCHO1 AR 619164 Low, poor proliferation Normal number Normal Recurrent infections (viral, mycobacterial, bacterial, fungal), lymphoproliferation, failure to thrive, increased activation-induced T-cell death, defective clathrin-mediated endocytosis 
PAX1 deficiency PAX1 AR 615560 Severe T-cell lymphopenia, low TRECs Normal number Normal Omenn-like syndrome (erythroderma, lymphocytosis, eosinophilia, severe/recurrent infections), no thymus, T-cell deficiency not corrected by HSCT. Otofaciocervical syndrome type 2, ear abnormalities 
ITPKB deficiency ITPKB AR NA Very few T cells Normal Normal IgM, IgA; low IgG FTT, recurrent bacterial/fungal infections, pan-leukopenia, anemia, thrombocytopenia 
SASH3 deficiency SASH3 XL 301082 T/NK cell lymphopenia B-cell lymphopenia Low, poor specific antibody responses Recurrent sinopulmonary, cutaneous and mucosal infections, refractory autoimmune cytopenia/neutropenia 
MAN2B2 deficiency MAN2B2 AR NA Low T cells Low B cells Normal/low Recurrent infections, vasculitis, arthritis, FTT, microcephaly, neurodevelopmental delay, congenital disorder of glycosylation 
COPG1 deficiency COPG1 AR 620983 T-cell lymphopenia Normal Normal but poor Ig response to vaccines Recurrent pneumonia, viral respiratory infections, chronic EBV, CMV viremia, FTT, bronchiectasis 
HELIOS deficiency IKZF2 AD
AR 		NA Increased activated T cells Normal number, reduced memory Reduced Recurrent upper respiratory infections/pneumonia, thrush, mucosal ulcers, chronic lymphadenopathy, SLE, ITP, AIHA (Evans syndrome), EBV-associated HLH, lymphoma 
IKKα deficiency CHUK AR NA Normal Reduced Low Recurrent bacterial, viral, fungal infections, absent secondary lymphoid tissues; skeletal abnormalities, FTT 
IRF4 multimorphic (IRF4 R95T) IRF4 AD-neomorph NA Normal counts of circulating T cells; normal proportions of naïve, CM, EM, and TEMRA CD4+T cells, reduced TCM, TEM, TEMRACD8+T-cell proportions; low TH17 and TFHcells Reduced CD19+cells; increased naïve B cells; reduced class-switched memory B cells; decreased plasmablasts and plasma cells Agammaglobulinemia or extremely low IgM, IgG, and IgA serum levels Early-onset recurrent sinopulmonary infections with P. jirovecii, pneumonia, severe viral disease (CMV and EBV), localized disease with weakly virulent (BCG vaccine) or pathogenic mycobacteria (Mycobacterium bovis), and chronic diarrhea 
Primary antibody deficiency/CID due to IRF4 variants IRF4 AD-neomorph NA Lymphocytes, low naïve CD4 and CD8 T cell counts, and high terminal effector CD4 and CD8 T cell counts   Hypogammaglobulinemia, low IgM, IgG, and IgA serum levels, early gray hairing 
NFATC1 deficiency NFATC1 AR NA Normal/increased proportions of CD8+T, lower proportions of naïve and TCMCD4+and CD8+T cells, increased TCMcells; lower proportions of Treg, TFH, TH1, TH2 Normal, low proportions of switched memory/increased proportions of naïve B cells Hypogammaglobulinemia, decreased or normal serum IgA, decreased serum IgG and IgM, low titers to pneumococcus and HBV vaccines Early-onset sinopulmonary infections with bronchiectasis. May present with recurrent warts, bacterial skin infections (folliculitis and abscesses). Scoliosis in 2 of 3 patients 
FOXI3 haploinsufficiency FOXI3 AD NA CD4 and CD8 T-cell lymphopenia Slightly decreased Normal Abnormal TRECS, thymus hypoplasia; increased head circumference 
PSMB10-associated OS PSMB10 p.Asp56His/p.Gly201Arg AD 620807 Low, skewed TCR repertoire. Low TRECs Low or absent Low OS (diarrhea, alopecia, rash). Severe and recurrent infections (candidiasis, disseminated VZV and CMV, pneumocystis pneumonia, skin infections).
Hypereosinophilia 

SCID/CID spectrum: infants with SCID who have maternal T-cell engraftment may have T cells in normal numbers that do not function normally; these cells may cause autoimmune cytopenias or graft-versus-host disease. Hypomorphic mutations in several of the genes that cause SCID may result in OS, or “leaky” SCID, or still less profound CID phenotypes. Both OS and leaky SCID can be associated with >300 autologous T cells/µl of peripheral blood and reduced, rather than absent, proliferative responses when compared to typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity, and CD4 T lymphopenia can be found in an allelic series of RAG1/2 and other SCID-associated genes. There can be clinical overlap between some genes listed here and those listed in Table 7.

SCID, severe combined immunodeficiency; CID, combined immunodeficiency; EBV, Epstein-Barr virus; MHC, major histocompatibility complex; HPV, human papillomavirus; Treg, T regulatory cell; XL, X-linked; AR, autosomal recessive; AD, autosomal dominant; LOF, loss of function; GOF, gain of function; FTT, failure to thrive; ADA, adenosine deaminase; OS, Omenn syndrome; CM, central memory; MAIT, mucosal associated invariant T cells; PJP, Pneumocystis jirovecii pneumonia.

Total number of mutant genes in Table 1: 73 (ZAP70 has two entries with different inheritance mechanisms and associated phenotypes, thus two different disorders).

New IEIs: 7, IRF4, NFATC1, PRIM1, FOXI3, POLD3, NUDCD, and PSMB10 (20, 26, 27, 28, 29, 30, 31, 32).

View large
Table 2.

CIDs with associated or syndromic features

DiseaseGenetic defectInheritanceOMIMT cellsB cellsIgAssociated features
1. Immunodeficiency with congenital thrombocytopenia 
Wiskott–Aldrich syndrome (WAS LOF) WAS XL 300392 Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3 Normal numbers Low IgM and antibody responses to polysaccharides, often high IgA and IgE Thrombocytopenia with small platelets, eczema, recurrent bacterial/viral infections, bloody diarrhea, lymphoma, autoimmune disease, IgA nephropathy. Patients with XL-thrombocytopenia have later onset of complications and more favorable life expectancy but eventually develop similar complications as observed in WAS 
WIP deficiency WIPF1 AR 602357 Reduced, defective lymphocyte responses to anti-CD3 Normal or low Normal, except for high IgE Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea; WAS protein absent 
Arp2/3-mediated filament branching defect ARPC1B AR 604223 Normal Normal numbers Normal except for high IgA and IgE Mild thrombocytopenia with normal-sized platelets, recurrent invasive infections; colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia; defective Arp2/3 filament branching 
IKZF2 DN (ICHAD syndrome) IKZF2 AD 606234 CD4 and CD8 T-cell lymphopenia with low TRECs Normal to low Normal or low. Response to vaccine antigen normal to low Recurrent respiratory and ear infections, pneumonia, and chronic lung disease. Early-onset immune dysregulation (atopic dermatitis and AIHA) and syndromic features including developmental delay, autism, sensorineural hearing loss, cleft palate and syndromic craniofacial features, abnormal teeth, athelia (absent nipples) 
2. DNA repair defects other than those listed inTable 1  
Ataxia–telangiectasia ATM AR 607585 Progressive decrease, poor proliferation to mitogens; may have low TRECs and T cells by NBS Normal Often low IgA, IgE, and IgG subclasses, increased IgM monomers; antibodies variably decreased Ataxia, telangiectasia especially of sclerae; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein; increased radiosensitivity, chromosomal instability, and chromosomal translocations 
Nijmegen breakage syndrome NBN AR 602667 Progressive decrease; may have low TRECs and T cells by NBS Variably reduced Often low IgA, IgE, and IgG subclasses, increased IgM; antibodies variably decreased Microcephaly, dysmorphic facies; lymphomas and solid tumors; increased radiosensitivity; chromosomal instability 
Bloom syndrome BLM AR 604610 Normal Normal Low Short stature, dysmorphic facies, sun-sensitive erythema; marrow failure; leukemia, lymphoma; chromosomal instability 
Immunodeficiency with centromeric instability and facial anomalies (ICF types 1, 2, 3, 4) DNMT3B AR 602900 Decreased or normal, responses to PHA may be decreased Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency Facial dysmorphic features, developmental delay, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
ZBTB24 AR 614064 Decreased or normal Facial dysmorphic features, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
CDCA7 AR 609937 Decreased or normal; responses to PHA may be decreased 
HELLS AR 603946 Decreased or normal 
PMS2 deficiency PMS2 AR 600259 Normal Low B cells, switched and nonswitched Low IgG and IgA, high IgM, abnormal antibody responses Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumors 
RNF168 deficiency (radiosensitivity, immune deficiency, dysmorphic features, learning difficulties [RIDDLE] syndrome) RNF168 AR 612688 Normal Normal Low IgG or IgA Short stature, mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity 
MCM4 deficiency MCM4 AR 602638 Normal Normal Normal NK cells: low number and function; viral infections (EBV, HSV, VZV); short stature; B-cell lymphoma; adrenal failure 
X-linked reticulate pigmentary disorder (POLA1 deficiency) POLA1 XL 301220 Not assessed Not assessed Not assessed Hyperpigmentation, characteristic facies, lung, and GI involvement. NK cell dysfunction. Recurrent viral infections. POLA1 is required for synthesis of cytosolic RNA:DNA; its deficiency leads to increased type I interferon; hypomorphic variants may present with hyperpigmentation and interferonopathy, without immunodeficiency 
POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome) POLE1 AR 174762 Normal; decreased T-cell proliferation Low memory B cells Low IgG2 and IgM, lack of antibody to PPS Recurrent respiratory infections, meningitis; facial dysmorphism, livedo, short stature 
POLE2 (polymerase ε subunit 2) deficiency POLE2 AR 602670 Lymphopenia, lack of TRECS at NBS, absent proliferation in response to antigens Very low Hypogammaglobulinemia Recurrent infections, disseminated BCG infections; autoimmunity (type 1 diabetes), hypothyroidism, facial dysmorphism 
Ligase I deficiency LIG1 AR 126391 Lymphopenia, increased γδ T cells, decreased mitogen response Normal Hypogammaglobulinemia, Reduced antibody responses Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells 
NSMCE3 deficiency NSMCE3 AR 608243 Decreased number, poor responses to mitogens and antigens Normal Normal IgG, IgA, normal to elevated IgM; decreased antibody responses to PPS Severe lung disease (possibly viral); thymic hypoplasia; chromosomal breakage, radiation sensitivity 
ERCC6L2 (Hebo deficiency) ERCC6L2 AR 615667 Lymphopenia Low Normal Facial dysmorphism, microcephaly; bone marrow failure 
GINS1 deficiency GINS1 AR 610608 Low or normal Low or normal High IgA, low IgM, and IgG Neutropenia; IUGR; NK cells very low 
MCM10 deficiency MCM10 AR 619313 Low or normal Low Normal IgM, IgA, decreased IgG Severe (fatal) CMV infection, HLH-like, phenocopies GINS1 and MCM4 deficiencies; ↓ NK cells and NK function 
GINS4 deficiency GINS4 AR 610611 Normal Normal Normal or increased Low NK cell numbers and function, neutropenia, recurrent infections including CMV and varicella, and recurrent herpes labialis; recurrent otitis, sinusitis, gingivitis and oral abscesses, pneumonia, gastrointestinal sepsis, intermittent diarrhea, intrauterine growth restriction, growth delay, cryptorchidism, tonsillar hypertrophy, recurrent fever 
Rothmund–Thomson syndrome RECQL4 AR 268400 Normal or low Normal or low Normal or low Variable immunodeficiency, recurrent infections, poikiloderma, hyperkeratosis, hair, skeletal dental, and gastrointestinal abnormalities, growth delay, increased cancer risk, especially osteosarcoma 
3. Thymic defects with additional congenital anomalies 
DiGeorge/velocardiofacial syndrome
Chromosome 22q11.2DS 		Large deletion (3 Mb) typically in chromosome 22 (TBX1) AD 602054 Decreased or normal, 5% have low TRECs at NBS and <1,500 CD3T cells/μl in neonatal period Normal Normal or decreased Hypoparathyroidism; conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability, schizophrenia and autoimmunity 
DiGeorge/velocardiofacial syndrome Unknown Sporadic  Decreased or normal 
TBX1 deficiency TBX1 AD 602054 Decreased or normal, may have low TRECs at NBS 
CHARGE syndrome CHD7 AD 608892 Decreased or normal, may have low TRECs at NBS; response to PHA may be decreased Normal Normal or decreased Coloboma of eye; heart anomaly; choanal atresia; intellectual disability; genital and ear anomalies, CNS malformation; some are SCID-like 
SEMA3E AD 608166 
Unknown   
Winged-helix nude FOXN1 deficiency FOXN1 AR 601705 Very low Normal Decreased Severe infections; abnormal thymic epithelium, immunodeficiency; congenital alopecia, nail dystrophy; neural tube defect 
FOXN1 haploinsufficiency or GOF FOXN1 AD 600838 Severe T-cell lymphopenia at birth, normalized by adulthood Normal/low Not assessed Recurrent, viral, and bacterial respiratory tract infections; skin involvement (eczema, dermatitis), nail dystrophy 
Chromosome 10p13-p14 DS (10p13-p14DS) Del10p13-p14 AD 601362 Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens; hypoplastic thymus may be present Normal Normal Hypoparathyroidism; renal disease; deafness; growth retardation; facial dysmorphism; cardiac defects may be present; recurrent infections +/- 
4. Immuno-osseous dysplasias 
Cartilage hair hypoplasia (CHH) RMRP AR 157660 Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation Normal Normal or reduced, antibodies variably decreased Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestine 
Schimke immuno-osseous dysplasia SMARCAL1 AR 606622 Decreased Normal Normal Short stature, spondyloepiphyseal dysplasia, IUGR; nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure 
MYSM1 deficiency MYSM1 AR 612176 T-cell lymphopenia, reduced naïve T cells, low NK cells B-cell deficiency Hypogammaglobulinemia Short stature; recurrent infections; congenital bone marrow failure, myelodysplasia; immunodeficiency affecting B cells and granulocytes; skeletal anomalies; cataracts; developmental delay 
MOPD1 deficiency (Roifman syndrome) RNU4ATAC AR 601428 Decreased NK cell function Decreased total and memory B cells Hypogammaglobulinemia, variably decreased specific antibodies Recurrent bacterial infections; lymphadenopathy; spondyloepiphyseal dysplasia, extreme IUGR; retinal dystrophy; facial dysmorphism; may present with microcephaly; short stature 
Immunoskeletal dysplasia with neurodevelopmental abnormalities (EXTL3 deficiency) EXTL3 AR 617425 Decreased Normal Decreased or normal Short stature; cervical spinal stenosis, neurodevelopmental impairment; eosinophilia; may have early infant mortality 
5. Syndromes associated with elevated IgE and/or atopic disease not listed elsewhere (hyper-IgE syndromes [HIES]) 
AD-HIES STAT3 deficiency (Job syndrome) STAT3 AD LOF (dominant negative) 147060 Normal overall; Th17, T follicular helper, MAIT, NKT cells decreased, Tregs may be increased; impaired responses to STAT3-activating cytokines Normal, reduced memory B cells, BAFF expression increased, impaired responses to STAT3-activating cytokines Very high IgE, specific antibody production decreased Distinctive facial features (broad nasal bridge); bacterial infections (boils, pulmonary abscesses, pneumatoceles) due to Staphylococcusaureus, secondary pulmonary aspergillosis, PJP; eczema, chronic mucocutaneous candidiasis (CMC); impaired acute phase response, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms 
IL-6 receptor deficiency IL6R AR 147880 Normal/increased, increased memory Th2 cells; reduced proportions of cTFh cells; normal responses to mitogens Normal total and memory B; reduced switched memory B Normal/low serum IgM, IgG, A. Very high IgE; specific antibody production low Atopic dermatitis (eczema), reduced inflammatory responses, recurrent skin and lung pyogenic bacterial infections, cold abscesses; high circulating IL-6 levels 
IL-6 signal transducer (IL-6ST) partial deficiency IL6ST AR 618523 Normal Th17 cells Reduced switched and nonswitched memory B cells High IgE, specific antibody production variably affected Eczema, bacterial infections, boils, recurrent respiratory tract infections (including pneumonia, bronchiectasis) pulmonary abscesses; eosinophilia; pneumatoceles; bone fractures; retention of primary teeth; craniosynostosis; scoliosis, impaired acute phase responses 
AD 619752 Normal numbers but high naïve, low central memory T cells, and low proportion of effector memory CD8 T cells.
Increased Th2, low frequencies of TFh and MAIT 		Normal total but low memory Normal IgM, G, A; hyper-IgE Dermatitis/eczema, eosinophilia, recurrent skin infections, pneumonia, bronchiectasis, pneumatoceles with severe secondary pulmonary aspergillosis, connective tissue defects (scoliosis, face, joints, fractures, palate, tooth retention). Phenocopies aspects of AR IL-6R and IL-11R deficiencies (due to unresponsiveness to these cytokines), as well as AD STAT3 and AR ZNF341 
IL-6ST complete deficiency IL6ST AR 619751 ND; death in utero or in neonatal period occurred for most affected individuals Fatal Stuve–Wiedemann-like syndrome; skeletal dysplasia, osteoporosis, hyperextensibility, lung dysfunction, renal abnormalities, thrombocytopenia, dermatitis, eczema. Defective acute phase response. Completely unresponsive to IL-6 family cytokines 
ZNF341 deficiency
AR-HIES 		ZNF341 AR 618282 Decreased Th17 proportion and low NK cell counts
High frequencies of naïve CD4+T cells. Low frequencies of CD4+ and CD8+ CM T cells 		Normal, reduced memory B cells, impaired responses to STAT3-activating cytokines High IgE and IgG, normal or subnormal specific antibody production Phenocopy of AD-HIES; atopic dermatitis/eczema, bacterial skin infections and abscesses (S. aureus), recurrent respiratory infections, lung abscesses and pneumatoceles; CMC; mild eosinophilia; mild facial dysmorphism; skeletal/connective tissue abnormalities (hyperextensible joints; bone fractures, retention of primary teeth) 
ERBIN deficiency ERBIN AD 606944 Increased circulating Treg Normal Moderately increased IgE Recurrent respiratory infections, susceptibility to S. aureus, eczema; hyperextensible joints, scoliosis; arterial dilatation in some patients 
Loeys–Dietz syndrome (TGFBR deficiency) TGFBR1 AD 609192 Normal Normal Elevated IgE Recurrent respiratory infections; eczema, food allergies; hyperextensible joints, scoliosis, retention of primary teeth; aortic aneurisms 
TGFBR2 610168 
SMAD3 613795 
Comel–Netherton syndrome SPINK5 AR 605010 Normal Normal numbers, low switched and nonswitched B cells High IgE and IgA, antibody variably decreased Congenital ichthyosis, bamboo hair, atopic diathesis; severe atopic manifestations, increased bacterial infections; failure to thrive 
PGM3 deficiency PGM3 AR 172100 CD8 and CD4 T cells may be decreased Low B and memory B cells Normal or elevated IgG and IgA, most with high IgE, eosinophilia Severe eczema; autoimmunity; bacterial (S. aureus) and viral infections; recurrent skin abscesses, otitis media, recurrent respiratory tract infection (pneumonia, bronchiectasis); candidiasis; eosinophilia; neutropenia; skeletal anomalies/dysplasia (joint hypermotility and aneurism formation): short stature, brachydactyly, dysmorphic facial features; mild intellectual disability and cognitive impairment, delayed CNS myelination in some affected individuals. Failure to thrive 
CARD11 deficiency (heterozygous DN) CARD11 AD LOF 617638 Normal number, but defective T-cell activation and proliferation. Skewing toward Th2 Normal to low High IgE, poor specific antibody production; impaired activation of both NF-κB and mTORC1 pathways Variable atopy, eczema, food allergies, eosinophilia; cutaneous viral infections, recurrent respiratory infections; lymphoma; CID 
STAT6 GOF STAT6 AD GOF 620532 Normal numbers. T cells show Th2 skewing Normal High IgE, normal IgG Early-onset severe allergic diseases, resistant atopic dermatitis, eosinophilic GI disease with reflux, dysphagia, and eosinophilic esophagitis, food allergies with anaphylaxis, asthma with interstitial lung disease and bronchiectasis. Eosinophilia. Recurrent skin and respiratory bacterial, viral, and fungal infections in ∼50%. Short stature, skeletal features 
6. Defects of vitamin B12 and folate metabolism 
Transcobalamin 2 deficiency TCN2 AR 613441 Normal Variable Decreased Megaloblastic anemia, pancytopenia; if untreated (B12) for prolonged periods results in intellectual disability 
SLC46A1/PCFT deficiency causing hereditary folate malabsorption SLC46A1 AR 229050 Variable numbers and activation profile Variable Decreased Megaloblastic anemia, failure to thrive; if untreated for prolonged periods results in intellectual disability 
Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency MTHFD1 AR 172460 Low thymic output, normal in vitro proliferation Low Decreased/poor antibody responses to conjugated polysaccharide antigens Recurrent bacterial infection, P. jirovecii; megaloblastic anemia; failure to thrive; neutropenia; seizures, intellectual disability; folate-responsive 
SLC19A1/PCFT deficiency causing hereditary folate malabsorption SLC19A1 AR 620603 Mitogen-induced T-cell proliferation was significantly reduced Slightly low Slightly decreased or borderline Recurrent infections, severe pneumonia, mucositis, megaloblastic folate–dependent anemia 
7. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID) 
EDA-ID due to NEMO/IKBKG deficiency (ectodermal dysplasia, immune deficiency) IKBKG XL 300248 Normal or decreased, TCR activation impaired Normal; low memory and isotype-switched B cells Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibodies to polysaccharide antigens Anhidrotic ectodermal dysplasia (in some); various infections (bacteria, mycobacteria, viruses, fungi); colitis; conical teeth, variable defects of skin, hair, and teeth; monocyte dysfunction 
EDA-ID due to IKBA GOF mutation NFKBIA AD GOF 164008 Normal total T cells, TCR activation impaired Normal B-cell numbers, impaired BCR activation, low memory and isotype-switched B cells Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens Anhidrotic ectodermal dysplasia. Various infections (bacteria, mycobacteria, viruses, fungi); colitis; variable defects of skin, hair, and teeth; T-cell and monocyte dysfunction 
EDA-ID due to IKBKB GOF mutation IKBKB AD GOF 618204 Decreased T cells, impaired TCR activation Normal number, poor function Reduced Recurrent bacterial, viral, fungal infections; variable ectodermal defects 
8. Calcium channel defects 
ORAI-1 deficiency ORAI1 AR 610277 Normal, defective TCR–mediated activation Normal Normal Autoimmunity; EDA; nonprogressive myopathy 
STIM1 deficiency STIM1 AR 605921 
CRACR2A deficiency CRACR2A AR NA Mild reduction in T-cell numbers Normal Low Later onset, chronic diarrhea, recurrent lower respiratory tract infections, including pneumonia 
ITPR3 ITPR3 AR NA Low T-cell numbers, impaired T-cell activation and proliferation Low. Trend to lower proliferation Low Charcot–Marie–Tooth in one patient. CID, ITP, AIHA. Recurrent infections, enteropathy 
9. Other defects 
Purine nucleoside phosphorylase (PNP) deficiency PNP AR 164050 Progressive decrease Normal Normal or low Autoimmune hemolytic anemia; neurological impairment 
Immunodeficiency with multiple intestinal atresias TTC7A AR 609332 Variable, but sometimes absent or low TRECs at NBS; may have SCID phenotype at birth Normal or low Markedly decreased IgG, IgM, IgA Bacterial (sepsis), fungal, viral infections; multiple intestinal atresias, often with intrauterine polyhydramnios and early demise 
Trichohepatoenteric syndrome TTC37 AR 222470 Impaired IFN-γ production Variably low numbers of switched memory B cells Hypogammaglobulinemia, may have low antibody responses Respiratory infections; IUGR; facial dysmorphic features, wooly hair; early-onset intractable diarrhea, liver cirrhosis; platelet abnormalities 
SKIV2L 614602 
VODI SP110 AR 604457 Normal (decreased memory T cells) Normal (decreased memory B cells) Decreased IgG, IgA, IgM, absent germinal center and tissue plasma cells Hepatic veno-occlusive disease; susceptibility to PJP pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystrophy 
BCL11B deficiency BCL11B AD 617237 Low, poor proliferation Normal Normal Congenital abnormalities, neonatal teeth, dysmorphic facies; absent corpus callosum, neurocognitive deficits 
EPG5 deficiency (Vici syndrome) EPG5 AR 615068 Profound depletion of CD4+ cells Defective Decreased (particularly IgG2) Agenesis of the corpus callosum; cataracts; cardiomyopathy; skin hypopigmentation; intellectual disability; microcephaly; recurrent infections, chronic mucocutaneous candidiasis 
HOIL1 deficiency RBCK1 AR 610924 Normal numbers Normal, decreased memory B cells Poor antibody responses to polysaccharides Bacterial infections; autoinflammation; amylopectinosis 
HOIP deficiency RNF31 AR 612487 Normal numbers Normal, decreased memory B cells Decreased Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia 
Hennekam lymphangiectasia–lymphedema syndrome CCBE1 AR 612753 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
FAT4 AR 612411 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
Activating de novo mutations in nuclear factor, erythroid 2–like (NFE2L2) NFE2L2 AD 617744 Not reported Decreased switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory and skin infections; growth retardation, developmental delay; white matter cerebral lesions; increased level of homocysteine; increased expression of stress response genes 
STAT5B deficiency STAT5B AR 245590 Modestly decreased, reduced Treg number and function Normal Hypergammaglobulinemia, increased IgE Growth hormone–insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity 
AD (dominant negative) 604260 Normal Normal Increased IgE Growth failure; eczema (no immune defects compared with AR STAT5 deficiency) 
Kabuki syndrome
(types 1 and 2) 		KMT2D AD 602113 Normal Normal Low IgA and occasionally low IgG Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature; intellectual disability; congenital heart defects; recurrent infections (otitis media, pneumonia) in 50% of patients; autoimmunity may be present 
KDM6A XL (females may be affected) 300128 
KMT2A deficiency (Wiedemann–Steiner syndrome) KMT2A AD 605130 Normal Decreased switched and nonswitched memory B cells Hypogammaglobulinemia, decreased antibody responses Respiratory infections; short stature; hypertelorism; hairy elbows; developmental delay, intellectual disability 
DIAPH1 deficiency DIAPH1 AR 616632 Reduced naïve T cells Decreased memory B cells Low IgM, normal IgG Seizures, cortical blindness, microcephaly syndrome (SCBMS); recurrent bacterial, viral, fungal infections; B lymphoma (3/7) 
AIOLOS deficiency IKZF3 AD 619437 Normal Reduced; impaired development Very low EBV susceptibility, recurrent sinopulmonary and respiratory infections, P. jirovecii, warts (HPV), Mycobacterium avium, B-cell malignancy. Haploinsufficiency shows autoimmunity and allergy 
CD28 deficiency CD28 AR 620901 Normal Normal Normal Susceptibility to HPV infection only 
SGPL1 deficiency SGPL1 AR 617575 Low Low Low maybe due to nephrotic syndrome Low or normal NK cells. Multiple bacterial infections. Nephrotic syndrome, adrenal insufficiency, ichthyosis/acanthosis, dyslipidemia, mild hypothyroidism, neurological defects 
PTCRA deficiency PTCRA AR 620931 Low T-cell counts in infancy. Total T-cell counts gradually increased to reach normal ranges. Low circulating naïve αβ T-cell counts, normal memory αβ T-cell counts and high naïve γδ T-cell counts, low TRECs Normal  Recurrent infections, lymphoproliferation, and/or autoimmunity and presence of autoantibodies. Some (6/10) individuals are healthy, and some can have small or no visible thymus. Low frequency of MAIT. High proportion of CD4−CD8−DN αβ T cells among naïve T cells 
FLT3L deficiency FLT3LG AR 620926 Normal Decreased Increased Hypoplastic anemia, monocytopenia, DC-penia, low/absence of dermal DCs. NK cells normal. Recurrent/persistent viral infections, severe warts, bacterial (pneumonia, otitis media, pharyngitis, cellulitis) and fungal infections. Recurrent diarrhea from early infancy, failure to thrive 
Chromosome 11q DS (Jacobsen syndrome) 11q23del AD 147791 Lymphopenia; low NK cells Decreased B cells and switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory infections; multiple warts; facial dysmorphism, growth retardation 
DiseaseGenetic defectInheritanceOMIMT cellsB cellsIgAssociated features
1. Immunodeficiency with congenital thrombocytopenia 
Wiskott–Aldrich syndrome (WAS LOF) WAS XL 300392 Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3 Normal numbers Low IgM and antibody responses to polysaccharides, often high IgA and IgE Thrombocytopenia with small platelets, eczema, recurrent bacterial/viral infections, bloody diarrhea, lymphoma, autoimmune disease, IgA nephropathy. Patients with XL-thrombocytopenia have later onset of complications and more favorable life expectancy but eventually develop similar complications as observed in WAS 
WIP deficiency WIPF1 AR 602357 Reduced, defective lymphocyte responses to anti-CD3 Normal or low Normal, except for high IgE Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea; WAS protein absent 
Arp2/3-mediated filament branching defect ARPC1B AR 604223 Normal Normal numbers Normal except for high IgA and IgE Mild thrombocytopenia with normal-sized platelets, recurrent invasive infections; colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia; defective Arp2/3 filament branching 
IKZF2 DN (ICHAD syndrome) IKZF2 AD 606234 CD4 and CD8 T-cell lymphopenia with low TRECs Normal to low Normal or low. Response to vaccine antigen normal to low Recurrent respiratory and ear infections, pneumonia, and chronic lung disease. Early-onset immune dysregulation (atopic dermatitis and AIHA) and syndromic features including developmental delay, autism, sensorineural hearing loss, cleft palate and syndromic craniofacial features, abnormal teeth, athelia (absent nipples) 
2. DNA repair defects other than those listed inTable 1  
Ataxia–telangiectasia ATM AR 607585 Progressive decrease, poor proliferation to mitogens; may have low TRECs and T cells by NBS Normal Often low IgA, IgE, and IgG subclasses, increased IgM monomers; antibodies variably decreased Ataxia, telangiectasia especially of sclerae; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein; increased radiosensitivity, chromosomal instability, and chromosomal translocations 
Nijmegen breakage syndrome NBN AR 602667 Progressive decrease; may have low TRECs and T cells by NBS Variably reduced Often low IgA, IgE, and IgG subclasses, increased IgM; antibodies variably decreased Microcephaly, dysmorphic facies; lymphomas and solid tumors; increased radiosensitivity; chromosomal instability 
Bloom syndrome BLM AR 604610 Normal Normal Low Short stature, dysmorphic facies, sun-sensitive erythema; marrow failure; leukemia, lymphoma; chromosomal instability 
Immunodeficiency with centromeric instability and facial anomalies (ICF types 1, 2, 3, 4) DNMT3B AR 602900 Decreased or normal, responses to PHA may be decreased Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency Facial dysmorphic features, developmental delay, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
ZBTB24 AR 614064 Decreased or normal Facial dysmorphic features, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
CDCA7 AR 609937 Decreased or normal; responses to PHA may be decreased 
HELLS AR 603946 Decreased or normal 
PMS2 deficiency PMS2 AR 600259 Normal Low B cells, switched and nonswitched Low IgG and IgA, high IgM, abnormal antibody responses Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumors 
RNF168 deficiency (radiosensitivity, immune deficiency, dysmorphic features, learning difficulties [RIDDLE] syndrome) RNF168 AR 612688 Normal Normal Low IgG or IgA Short stature, mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity 
MCM4 deficiency MCM4 AR 602638 Normal Normal Normal NK cells: low number and function; viral infections (EBV, HSV, VZV); short stature; B-cell lymphoma; adrenal failure 
X-linked reticulate pigmentary disorder (POLA1 deficiency) POLA1 XL 301220 Not assessed Not assessed Not assessed Hyperpigmentation, characteristic facies, lung, and GI involvement. NK cell dysfunction. Recurrent viral infections. POLA1 is required for synthesis of cytosolic RNA:DNA; its deficiency leads to increased type I interferon; hypomorphic variants may present with hyperpigmentation and interferonopathy, without immunodeficiency 
POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome) POLE1 AR 174762 Normal; decreased T-cell proliferation Low memory B cells Low IgG2 and IgM, lack of antibody to PPS Recurrent respiratory infections, meningitis; facial dysmorphism, livedo, short stature 
POLE2 (polymerase ε subunit 2) deficiency POLE2 AR 602670 Lymphopenia, lack of TRECS at NBS, absent proliferation in response to antigens Very low Hypogammaglobulinemia Recurrent infections, disseminated BCG infections; autoimmunity (type 1 diabetes), hypothyroidism, facial dysmorphism 
Ligase I deficiency LIG1 AR 126391 Lymphopenia, increased γδ T cells, decreased mitogen response Normal Hypogammaglobulinemia, Reduced antibody responses Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells 
NSMCE3 deficiency NSMCE3 AR 608243 Decreased number, poor responses to mitogens and antigens Normal Normal IgG, IgA, normal to elevated IgM; decreased antibody responses to PPS Severe lung disease (possibly viral); thymic hypoplasia; chromosomal breakage, radiation sensitivity 
ERCC6L2 (Hebo deficiency) ERCC6L2 AR 615667 Lymphopenia Low Normal Facial dysmorphism, microcephaly; bone marrow failure 
GINS1 deficiency GINS1 AR 610608 Low or normal Low or normal High IgA, low IgM, and IgG Neutropenia; IUGR; NK cells very low 
MCM10 deficiency MCM10 AR 619313 Low or normal Low Normal IgM, IgA, decreased IgG Severe (fatal) CMV infection, HLH-like, phenocopies GINS1 and MCM4 deficiencies; ↓ NK cells and NK function 
GINS4 deficiency GINS4 AR 610611 Normal Normal Normal or increased Low NK cell numbers and function, neutropenia, recurrent infections including CMV and varicella, and recurrent herpes labialis; recurrent otitis, sinusitis, gingivitis and oral abscesses, pneumonia, gastrointestinal sepsis, intermittent diarrhea, intrauterine growth restriction, growth delay, cryptorchidism, tonsillar hypertrophy, recurrent fever 
Rothmund–Thomson syndrome RECQL4 AR 268400 Normal or low Normal or low Normal or low Variable immunodeficiency, recurrent infections, poikiloderma, hyperkeratosis, hair, skeletal dental, and gastrointestinal abnormalities, growth delay, increased cancer risk, especially osteosarcoma 
3. Thymic defects with additional congenital anomalies 
DiGeorge/velocardiofacial syndrome
Chromosome 22q11.2DS 		Large deletion (3 Mb) typically in chromosome 22 (TBX1) AD 602054 Decreased or normal, 5% have low TRECs at NBS and <1,500 CD3T cells/μl in neonatal period Normal Normal or decreased Hypoparathyroidism; conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability, schizophrenia and autoimmunity 
DiGeorge/velocardiofacial syndrome Unknown Sporadic  Decreased or normal 
TBX1 deficiency TBX1 AD 602054 Decreased or normal, may have low TRECs at NBS 
CHARGE syndrome CHD7 AD 608892 Decreased or normal, may have low TRECs at NBS; response to PHA may be decreased Normal Normal or decreased Coloboma of eye; heart anomaly; choanal atresia; intellectual disability; genital and ear anomalies, CNS malformation; some are SCID-like 
SEMA3E AD 608166 
Unknown   
Winged-helix nude FOXN1 deficiency FOXN1 AR 601705 Very low Normal Decreased Severe infections; abnormal thymic epithelium, immunodeficiency; congenital alopecia, nail dystrophy; neural tube defect 
FOXN1 haploinsufficiency or GOF FOXN1 AD 600838 Severe T-cell lymphopenia at birth, normalized by adulthood Normal/low Not assessed Recurrent, viral, and bacterial respiratory tract infections; skin involvement (eczema, dermatitis), nail dystrophy 
Chromosome 10p13-p14 DS (10p13-p14DS) Del10p13-p14 AD 601362 Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens; hypoplastic thymus may be present Normal Normal Hypoparathyroidism; renal disease; deafness; growth retardation; facial dysmorphism; cardiac defects may be present; recurrent infections +/- 
4. Immuno-osseous dysplasias 
Cartilage hair hypoplasia (CHH) RMRP AR 157660 Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation Normal Normal or reduced, antibodies variably decreased Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestine 
Schimke immuno-osseous dysplasia SMARCAL1 AR 606622 Decreased Normal Normal Short stature, spondyloepiphyseal dysplasia, IUGR; nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure 
MYSM1 deficiency MYSM1 AR 612176 T-cell lymphopenia, reduced naïve T cells, low NK cells B-cell deficiency Hypogammaglobulinemia Short stature; recurrent infections; congenital bone marrow failure, myelodysplasia; immunodeficiency affecting B cells and granulocytes; skeletal anomalies; cataracts; developmental delay 
MOPD1 deficiency (Roifman syndrome) RNU4ATAC AR 601428 Decreased NK cell function Decreased total and memory B cells Hypogammaglobulinemia, variably decreased specific antibodies Recurrent bacterial infections; lymphadenopathy; spondyloepiphyseal dysplasia, extreme IUGR; retinal dystrophy; facial dysmorphism; may present with microcephaly; short stature 
Immunoskeletal dysplasia with neurodevelopmental abnormalities (EXTL3 deficiency) EXTL3 AR 617425 Decreased Normal Decreased or normal Short stature; cervical spinal stenosis, neurodevelopmental impairment; eosinophilia; may have early infant mortality 
5. Syndromes associated with elevated IgE and/or atopic disease not listed elsewhere (hyper-IgE syndromes [HIES]) 
AD-HIES STAT3 deficiency (Job syndrome) STAT3 AD LOF (dominant negative) 147060 Normal overall; Th17, T follicular helper, MAIT, NKT cells decreased, Tregs may be increased; impaired responses to STAT3-activating cytokines Normal, reduced memory B cells, BAFF expression increased, impaired responses to STAT3-activating cytokines Very high IgE, specific antibody production decreased Distinctive facial features (broad nasal bridge); bacterial infections (boils, pulmonary abscesses, pneumatoceles) due to Staphylococcusaureus, secondary pulmonary aspergillosis, PJP; eczema, chronic mucocutaneous candidiasis (CMC); impaired acute phase response, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms 
IL-6 receptor deficiency IL6R AR 147880 Normal/increased, increased memory Th2 cells; reduced proportions of cTFh cells; normal responses to mitogens Normal total and memory B; reduced switched memory B Normal/low serum IgM, IgG, A. Very high IgE; specific antibody production low Atopic dermatitis (eczema), reduced inflammatory responses, recurrent skin and lung pyogenic bacterial infections, cold abscesses; high circulating IL-6 levels 
IL-6 signal transducer (IL-6ST) partial deficiency IL6ST AR 618523 Normal Th17 cells Reduced switched and nonswitched memory B cells High IgE, specific antibody production variably affected Eczema, bacterial infections, boils, recurrent respiratory tract infections (including pneumonia, bronchiectasis) pulmonary abscesses; eosinophilia; pneumatoceles; bone fractures; retention of primary teeth; craniosynostosis; scoliosis, impaired acute phase responses 
AD 619752 Normal numbers but high naïve, low central memory T cells, and low proportion of effector memory CD8 T cells.
Increased Th2, low frequencies of TFh and MAIT 		Normal total but low memory Normal IgM, G, A; hyper-IgE Dermatitis/eczema, eosinophilia, recurrent skin infections, pneumonia, bronchiectasis, pneumatoceles with severe secondary pulmonary aspergillosis, connective tissue defects (scoliosis, face, joints, fractures, palate, tooth retention). Phenocopies aspects of AR IL-6R and IL-11R deficiencies (due to unresponsiveness to these cytokines), as well as AD STAT3 and AR ZNF341 
IL-6ST complete deficiency IL6ST AR 619751 ND; death in utero or in neonatal period occurred for most affected individuals Fatal Stuve–Wiedemann-like syndrome; skeletal dysplasia, osteoporosis, hyperextensibility, lung dysfunction, renal abnormalities, thrombocytopenia, dermatitis, eczema. Defective acute phase response. Completely unresponsive to IL-6 family cytokines 
ZNF341 deficiency
AR-HIES 		ZNF341 AR 618282 Decreased Th17 proportion and low NK cell counts
High frequencies of naïve CD4+T cells. Low frequencies of CD4+ and CD8+ CM T cells 		Normal, reduced memory B cells, impaired responses to STAT3-activating cytokines High IgE and IgG, normal or subnormal specific antibody production Phenocopy of AD-HIES; atopic dermatitis/eczema, bacterial skin infections and abscesses (S. aureus), recurrent respiratory infections, lung abscesses and pneumatoceles; CMC; mild eosinophilia; mild facial dysmorphism; skeletal/connective tissue abnormalities (hyperextensible joints; bone fractures, retention of primary teeth) 
ERBIN deficiency ERBIN AD 606944 Increased circulating Treg Normal Moderately increased IgE Recurrent respiratory infections, susceptibility to S. aureus, eczema; hyperextensible joints, scoliosis; arterial dilatation in some patients 
Loeys–Dietz syndrome (TGFBR deficiency) TGFBR1 AD 609192 Normal Normal Elevated IgE Recurrent respiratory infections; eczema, food allergies; hyperextensible joints, scoliosis, retention of primary teeth; aortic aneurisms 
TGFBR2 610168 
SMAD3 613795 
Comel–Netherton syndrome SPINK5 AR 605010 Normal Normal numbers, low switched and nonswitched B cells High IgE and IgA, antibody variably decreased Congenital ichthyosis, bamboo hair, atopic diathesis; severe atopic manifestations, increased bacterial infections; failure to thrive 
PGM3 deficiency PGM3 AR 172100 CD8 and CD4 T cells may be decreased Low B and memory B cells Normal or elevated IgG and IgA, most with high IgE, eosinophilia Severe eczema; autoimmunity; bacterial (S. aureus) and viral infections; recurrent skin abscesses, otitis media, recurrent respiratory tract infection (pneumonia, bronchiectasis); candidiasis; eosinophilia; neutropenia; skeletal anomalies/dysplasia (joint hypermotility and aneurism formation): short stature, brachydactyly, dysmorphic facial features; mild intellectual disability and cognitive impairment, delayed CNS myelination in some affected individuals. Failure to thrive 
CARD11 deficiency (heterozygous DN) CARD11 AD LOF 617638 Normal number, but defective T-cell activation and proliferation. Skewing toward Th2 Normal to low High IgE, poor specific antibody production; impaired activation of both NF-κB and mTORC1 pathways Variable atopy, eczema, food allergies, eosinophilia; cutaneous viral infections, recurrent respiratory infections; lymphoma; CID 
STAT6 GOF STAT6 AD GOF 620532 Normal numbers. T cells show Th2 skewing Normal High IgE, normal IgG Early-onset severe allergic diseases, resistant atopic dermatitis, eosinophilic GI disease with reflux, dysphagia, and eosinophilic esophagitis, food allergies with anaphylaxis, asthma with interstitial lung disease and bronchiectasis. Eosinophilia. Recurrent skin and respiratory bacterial, viral, and fungal infections in ∼50%. Short stature, skeletal features 
6. Defects of vitamin B12 and folate metabolism 
Transcobalamin 2 deficiency TCN2 AR 613441 Normal Variable Decreased Megaloblastic anemia, pancytopenia; if untreated (B12) for prolonged periods results in intellectual disability 
SLC46A1/PCFT deficiency causing hereditary folate malabsorption SLC46A1 AR 229050 Variable numbers and activation profile Variable Decreased Megaloblastic anemia, failure to thrive; if untreated for prolonged periods results in intellectual disability 
Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency MTHFD1 AR 172460 Low thymic output, normal in vitro proliferation Low Decreased/poor antibody responses to conjugated polysaccharide antigens Recurrent bacterial infection, P. jirovecii; megaloblastic anemia; failure to thrive; neutropenia; seizures, intellectual disability; folate-responsive 
SLC19A1/PCFT deficiency causing hereditary folate malabsorption SLC19A1 AR 620603 Mitogen-induced T-cell proliferation was significantly reduced Slightly low Slightly decreased or borderline Recurrent infections, severe pneumonia, mucositis, megaloblastic folate–dependent anemia 
7. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID) 
EDA-ID due to NEMO/IKBKG deficiency (ectodermal dysplasia, immune deficiency) IKBKG XL 300248 Normal or decreased, TCR activation impaired Normal; low memory and isotype-switched B cells Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibodies to polysaccharide antigens Anhidrotic ectodermal dysplasia (in some); various infections (bacteria, mycobacteria, viruses, fungi); colitis; conical teeth, variable defects of skin, hair, and teeth; monocyte dysfunction 
EDA-ID due to IKBA GOF mutation NFKBIA AD GOF 164008 Normal total T cells, TCR activation impaired Normal B-cell numbers, impaired BCR activation, low memory and isotype-switched B cells Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens Anhidrotic ectodermal dysplasia. Various infections (bacteria, mycobacteria, viruses, fungi); colitis; variable defects of skin, hair, and teeth; T-cell and monocyte dysfunction 
EDA-ID due to IKBKB GOF mutation IKBKB AD GOF 618204 Decreased T cells, impaired TCR activation Normal number, poor function Reduced Recurrent bacterial, viral, fungal infections; variable ectodermal defects 
8. Calcium channel defects 
ORAI-1 deficiency ORAI1 AR 610277 Normal, defective TCR–mediated activation Normal Normal Autoimmunity; EDA; nonprogressive myopathy 
STIM1 deficiency STIM1 AR 605921 
CRACR2A deficiency CRACR2A AR NA Mild reduction in T-cell numbers Normal Low Later onset, chronic diarrhea, recurrent lower respiratory tract infections, including pneumonia 
ITPR3 ITPR3 AR NA Low T-cell numbers, impaired T-cell activation and proliferation Low. Trend to lower proliferation Low Charcot–Marie–Tooth in one patient. CID, ITP, AIHA. Recurrent infections, enteropathy 
9. Other defects 
Purine nucleoside phosphorylase (PNP) deficiency PNP AR 164050 Progressive decrease Normal Normal or low Autoimmune hemolytic anemia; neurological impairment 
Immunodeficiency with multiple intestinal atresias TTC7A AR 609332 Variable, but sometimes absent or low TRECs at NBS; may have SCID phenotype at birth Normal or low Markedly decreased IgG, IgM, IgA Bacterial (sepsis), fungal, viral infections; multiple intestinal atresias, often with intrauterine polyhydramnios and early demise 
Trichohepatoenteric syndrome TTC37 AR 222470 Impaired IFN-γ production Variably low numbers of switched memory B cells Hypogammaglobulinemia, may have low antibody responses Respiratory infections; IUGR; facial dysmorphic features, wooly hair; early-onset intractable diarrhea, liver cirrhosis; platelet abnormalities 
SKIV2L 614602 
VODI SP110 AR 604457 Normal (decreased memory T cells) Normal (decreased memory B cells) Decreased IgG, IgA, IgM, absent germinal center and tissue plasma cells Hepatic veno-occlusive disease; susceptibility to PJP pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystrophy 
BCL11B deficiency BCL11B AD 617237 Low, poor proliferation Normal Normal Congenital abnormalities, neonatal teeth, dysmorphic facies; absent corpus callosum, neurocognitive deficits 
EPG5 deficiency (Vici syndrome) EPG5 AR 615068 Profound depletion of CD4+ cells Defective Decreased (particularly IgG2) Agenesis of the corpus callosum; cataracts; cardiomyopathy; skin hypopigmentation; intellectual disability; microcephaly; recurrent infections, chronic mucocutaneous candidiasis 
HOIL1 deficiency RBCK1 AR 610924 Normal numbers Normal, decreased memory B cells Poor antibody responses to polysaccharides Bacterial infections; autoinflammation; amylopectinosis 
HOIP deficiency RNF31 AR 612487 Normal numbers Normal, decreased memory B cells Decreased Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia 
Hennekam lymphangiectasia–lymphedema syndrome CCBE1 AR 612753 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
FAT4 AR 612411 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
Activating de novo mutations in nuclear factor, erythroid 2–like (NFE2L2) NFE2L2 AD 617744 Not reported Decreased switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory and skin infections; growth retardation, developmental delay; white matter cerebral lesions; increased level of homocysteine; increased expression of stress response genes 
STAT5B deficiency STAT5B AR 245590 Modestly decreased, reduced Treg number and function Normal Hypergammaglobulinemia, increased IgE Growth hormone–insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity 
AD (dominant negative) 604260 Normal Normal Increased IgE Growth failure; eczema (no immune defects compared with AR STAT5 deficiency) 
Kabuki syndrome
(types 1 and 2) 		KMT2D AD 602113 Normal Normal Low IgA and occasionally low IgG Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature; intellectual disability; congenital heart defects; recurrent infections (otitis media, pneumonia) in 50% of patients; autoimmunity may be present 
KDM6A XL (females may be affected) 300128 
KMT2A deficiency (Wiedemann–Steiner syndrome) KMT2A AD 605130 Normal Decreased switched and nonswitched memory B cells Hypogammaglobulinemia, decreased antibody responses Respiratory infections; short stature; hypertelorism; hairy elbows; developmental delay, intellectual disability 
DIAPH1 deficiency DIAPH1 AR 616632 Reduced naïve T cells Decreased memory B cells Low IgM, normal IgG Seizures, cortical blindness, microcephaly syndrome (SCBMS); recurrent bacterial, viral, fungal infections; B lymphoma (3/7) 
AIOLOS deficiency IKZF3 AD 619437 Normal Reduced; impaired development Very low EBV susceptibility, recurrent sinopulmonary and respiratory infections, P. jirovecii, warts (HPV), Mycobacterium avium, B-cell malignancy. Haploinsufficiency shows autoimmunity and allergy 
CD28 deficiency CD28 AR 620901 Normal Normal Normal Susceptibility to HPV infection only 
SGPL1 deficiency SGPL1 AR 617575 Low Low Low maybe due to nephrotic syndrome Low or normal NK cells. Multiple bacterial infections. Nephrotic syndrome, adrenal insufficiency, ichthyosis/acanthosis, dyslipidemia, mild hypothyroidism, neurological defects 
PTCRA deficiency PTCRA AR 620931 Low T-cell counts in infancy. Total T-cell counts gradually increased to reach normal ranges. Low circulating naïve αβ T-cell counts, normal memory αβ T-cell counts and high naïve γδ T-cell counts, low TRECs Normal  Recurrent infections, lymphoproliferation, and/or autoimmunity and presence of autoantibodies. Some (6/10) individuals are healthy, and some can have small or no visible thymus. Low frequency of MAIT. High proportion of CD4−CD8−DN αβ T cells among naïve T cells 
FLT3L deficiency FLT3LG AR 620926 Normal Decreased Increased Hypoplastic anemia, monocytopenia, DC-penia, low/absence of dermal DCs. NK cells normal. Recurrent/persistent viral infections, severe warts, bacterial (pneumonia, otitis media, pharyngitis, cellulitis) and fungal infections. Recurrent diarrhea from early infancy, failure to thrive 
Chromosome 11q DS (Jacobsen syndrome) 11q23del AD 147791 Lymphopenia; low NK cells Decreased B cells and switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory infections; multiple warts; facial dysmorphism, growth retardation 

EDA, ectodermal dysplasia, anhidrotic; HSV, herpes simplex virus; VZV, varicella zoster virus; BCG; bacillus Calmette–Guerin; NBS, newborn screen; TREC, T-cell receptor excision circle (biomarker for low T cells used in NBS); IUGR, intrauterine growth retardation; CID, combined immune deficiency; ITP, idiopathic thrombocytopenic purpura; AIHA, autoimmune hemolytic anemia; SCID, severe combined immunodeficiency; CID, combined immunodeficiency; CNS, central nervous system; HIES, hyper-IgE syndromes; HPV, human papillomavirus; Ab, antibody; EDA-ID, ectodermodysplasia with immunodeficiency; PJP, Pneumocystis jirovecii pneumonia.

Total number of mutant genes in Table 2: 83 including two entries for IL-6ST, two entries for STAT5B, and two for FOXN1 with distinct but partially overlapping phenotypes.

New IEIs: 10, dominant negative IKZF2, GINS4, STAT6 GOF, SMAD3, SLC19A1, SGPL1, PTCRA, FLT3L, ITPR3, and RECQL4 (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47).

Unknown cause of DiGeorge syndrome, unknown cause of CHARGE syndrome, unknown gene(s) within 10p13-14 deletion responsible for phenotype.

View large
Table 3.

Predominantly antibody deficiencies

DiseaseGenetic defectInheritanceOMIMIgAssociated features
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia 
BTK deficiency, X-linked agammaglobulinemia BTK XL 300300 All isotypes decreased in majority of patients; some patients have detectable immunoglobulins Severe bacterial infections, normal numbers of pro-B cells 
μ heavy chain deficiency IGHM AR 147020 All isotypes decreased Severe bacterial infections, normal numbers of pro-B cells 
λ5 deficiency IGLL1 AR 146770 
Igα deficiency CD79A AR 112205 
Igβ deficiency CD79B AR 147245 
BLNK deficiency BLNK AR 604515 
p110δ deficiency PIK3CD AR 602839 Severe bacterial infections; autoimmune complications (IBD) 
p85 deficiency PIK3R1 AR 615214 Severe bacterial infections, cytopenias, decreased or absent pro-B cells 
E47 transcription factor deficiency TCF3 AD 616941 Recurrent bacterial infections 
AR 619824 Severe, recurrent bacterial infections, failure to thrive 
SLC39A7 (ZIP7) deficiency SLC39A7 AR 601416 Early-onset infections, blistering dermatosis, failure to thrive, thrombocytopenia 
Hoffman syndrome/TOP2B deficiency TOP2B AD 126431 Recurrent infections, facial dysmorphism, limb anomalies 
FNIP1 deficiency (6 patients) FNIP1 AR 619705 Early-onset recurrent infections, bronchiectasis, fibrosis, interstitial pneumonia; neutropenia (severe or intermittent); Crohn’s disease (one patient); congenital heart defects, muscular hypotonia; developmental delay 
PU1 deficiency SPI1 AD 619707 Sinopulmonary infections with encapsulated bacteria, viral infections 
PAX5 deficiency (n = 1) PAX5 AR   Early B-cell developmental block, B cell strongly decreased, transitional and naïve mature B cells expressed lower CD19 and IgD—natural effector and memory B cells, as well as plasmablasts, were absent in the blood of the patient; a-/hypo-gammaglobulinemia, recurrent infections, autism spectrum disorder (ASD), and sensorimotor and cognitive defects 
2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID phenotype 
Common variable immune deficiency with no gene defect specified (CVID) Unknown Variable NA Low IgG and IgA and/or IgM Clinical phenotypes vary most have recurrent infections; some have polyclonal lymphoproliferation, autoimmune cytopenias, and/or granulomatous disease 
Activated p110δ syndrome (APDS) PIK3CD GOF AD 615513 (APDS1) Normal/increased IgM, reduced IgG and IgA Severe bacterial infections, reduced memory B cells, and increased transitional B cells, EBV ± CMV viremia, lymphadenopathy/splenomegaly, autoimmunity, lymphoproliferation, lymphoma 
PIK3R1 AD 616005 (APDS2) Severe bacterial infections, reduced memory B cells, and increased transitional B cells, lymphadenopathy/splenomegaly, lymphoproliferation, lymphoma; developmental delay 
PTEN deficiency (LOF) PTEN AD 158350 Normal/decreased Recurrent infections, lymphoproliferation, autoimmunity; developmental delay 
CD19 deficiency CD19 AR 107265 Low IgG and IgA and/or IgM Recurrent infections, may have glomerulonephritis (CD81 mutation abolishes the expression of CD19, thereby phenocopying CD19 mutations) 
CD81 deficiency CD81 AR 186845 Low IgG, low or normal IgA and IgM 
CD20 deficiency MS4A1(CD20) AR 112210 Low IgG, normal or elevated IgM and IgA Recurrent infections 
CD21 deficiency CR2 (CD21) AR 120650 Low IgG, impaired anti-pneumococcal response Recurrent infections 
TACI deficiencya TNFRSF13B AR or AD 604907 Low IgG and IgA and/or IgM Variable clinical expression and penetrance for monoallelic variants 
BAFF receptor deficiency TNFRSF13C AR 606269 Low IgG and IgM Variable clinical expression 
TWEAK deficiency TNFSF12 AD 602695 Low IgM and IgA, lack of anti-pneumococcal antibody Pneumonia, bacterial infections, warts, thrombocytopenia, neutropenia 
TRNT1 deficiency TRNT1 AR 612907 B-cell deficiency and hypogammaglobulinemia Congenital sideroblastic anemia, deafness, developmental delay 
NFKB1 deficiency NFKB1 AD 164011 Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells Recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia, and autoimmune thyroiditis 
NFKB2 deficiency NFKB2 AD 615577 Low serum IgG, IgA, and IgM; low B-cell numbers Recurrent sinopulmonary infections, alopecia, and endocrinopathies 
IKAROS deficiency IKZF1 AD (haploinsufficiency) 603023 Low IgG, IgA, IgM, low or normal B cells; B cells and Ig levels reduce with age Decreased pro-B cells, recurrent sinopulmonary infections; increased risk of ALL, autoimmunity, CVID phenotype 
IRF2BP2 deficiency IRF2BP2 AD 615332 Hypogammaglobulinemia, absent IgA Recurrent infections, possible autoimmunity and inflammatory disease 
ATP6AP1 deficiency ATP6AP1 XL 300972 Variable immunoglobulin findings Hepatopathy, leukopenia, low copper 
ARHGEF1 deficiency ARHGEF1 AR 618459 Hypogammaglobulinemia; lack of antibody Recurrent infections, bronchiectasis 
SH3KBP1 (CIN85) deficiency SH3KBP1 XL 300310 IgM, IgG deficiency; loss of antibody Severe bacterial infections 
SEC61A1 deficiency SEC61A1 AD 609213 Hypogammaglobulinemia Severe recurrent respiratory tract infections 
RAC2 deficiency RAC2 AR 602049 Low IgG, IgA, IgM, low or normal B cells; reduced Ab responses following vaccination Recurrent sinopulmonary infections, selective IgA deficiency; poststreptococcal glomerulonephritis; urticaria 
Mannosyl-oligosaccharide glucosidase deficiency MOGS AR 601336 Low IgG, IgA, IgM, increased B cells; poor Ab responses following vaccination Bacterial and viral infections; severe neurological disease; also known as congenital disorder of glycosylation type IIb (CDG-IIb) 
PIK3CG deficiency PIK3CG AR 619802 Reduced memory B cells, hypogammaglobulinemia Recurrent infections, cytopenia/lymphopenia, eosinophilia, splenomegaly, lymphadenopathy, HLH-like 
BOB1 deficiency POU2AF1 AR NA Reduced memory B cells, agammaglobulinemia Recurrent respiratory infections, possible chronic viral infection of CNS with progressive tetraparesis 
KARS1 deficiency KARS1 AR 619147 Impaired B-cell metabolism (decreased mitochondrial numbers and activity). B-cell lymphopenia, hypogammaglobulinemia, impaired vaccine responses Severe developmental delay, sensorineural deafness, acute disseminated encephalomyelitis, central and peripheral nervous system impairment, heart and liver disease. Recurrent/severe infections 
PI4KA deficiency PI4KA AR 619708 Reduced total B cells, few memory B cells, hypogammaglobulinemia Recurrent infections; autoimmune/autoinflammatory, neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus with polymicrogyria, cerebellar hypoplasia, arthrogryposis), and gastrointestinal (inflammatory bowel disease, multiple intestinal atresia) manifestations 
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper-IgM 
AID deficiency AICDA AR 605258 IgG and IgA decreased, IgM increased; normal memory B cells but lacking somatic hypermutation Bacterial infections, enlarged lymph nodes and germinal centers; autoimmunity 
AD NA IgG absent or decreased, IgA undetected, IgM increased; normal memory B cells with intact somatic hypermutation Bacterial infections, enlarged lymph nodes and germinal centers. Variants uniquely localize to the nuclear export signal 
UNG deficiency UNG AR 191525 IgG and IgA decreased, IgM increased Enlarged lymph nodes and germinal centers 
INO80 deficiency INO80 AR 610169 IgG and IgA decreased, IgM increased Severe bacterial infections 
MSH6 deficiency MSH6 AR 600678 Variable IgG, defects, increased IgM in some, normal B cells, low switched memory B cells, Ig class switch recombination and somatic hypermutation defects Family or personal history of cancer 
CTNNBL1 deficiency CTNNBL1 AR 619846 Reduced memory B cells, Ig class switch recombination and somatic hypermutation defects, progressive hypogammaglobulinemia CVID, autoimmune cytopenias, recurrent infections, hyperplastic germinal centers 
APRIL deficiency TNFSF13 AR NA Normal total B-cell counts, reduced memory B cells, hypogammaglobulinemia CVID, chronic but mild infections, alopecia areata 
4. Isotype, light chain, or functional deficiencies with generally normal numbers of B cells 
Ig heavy chain mutations and deletions Mutation or chromosomal deletion at 14q32 AR  One or more IgG and/or IgA subclasses, as well as IgE, may be absent May be asymptomatic 
Kappa chain deficiency IGKC AR 147200 All immunoglobulins have lambda light chain Asymptomatic 
Isolated IgG subclass deficiency Unknown ND  Reduction in one or more IgG subclass Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections 
IgG subclass deficiency with IgA deficiency Unknown ND  Reduced IgA with a decrease in one or more IgG subclass Recurrent bacterial infections
May be asymptomatic 
Selective IgA deficiency Unknown ND  Absent IgA with other isotypes normal, normal subclasses, and specific antibodies May be asymptomatic
Bacterial infections, autoimmunity mildly increased 
Specific antibody deficiency with normal Ig levels and normal B cells Unknown ND  Normal Reduced ability to produce antibodies to specific antigens 
Transient hypogammaglobulinemia of infancy Unknown ND  IgG and IgA decreased Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections 
CARD11 GOF CARD11 AD GOF 616452 Polyclonal B-cell lymphocytosis due to constitutive NF-κB activation Splenomegaly, lymphadenopathy, poor vaccine response 
Selective IgM deficiency Unknown ND  Absent serum IgM Pneumococcal/bacterial 
DiseaseGenetic defectInheritanceOMIMIgAssociated features
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia 
BTK deficiency, X-linked agammaglobulinemia BTK XL 300300 All isotypes decreased in majority of patients; some patients have detectable immunoglobulins Severe bacterial infections, normal numbers of pro-B cells 
μ heavy chain deficiency IGHM AR 147020 All isotypes decreased Severe bacterial infections, normal numbers of pro-B cells 
λ5 deficiency IGLL1 AR 146770 
Igα deficiency CD79A AR 112205 
Igβ deficiency CD79B AR 147245 
BLNK deficiency BLNK AR 604515 
p110δ deficiency PIK3CD AR 602839 Severe bacterial infections; autoimmune complications (IBD) 
p85 deficiency PIK3R1 AR 615214 Severe bacterial infections, cytopenias, decreased or absent pro-B cells 
E47 transcription factor deficiency TCF3 AD 616941 Recurrent bacterial infections 
AR 619824 Severe, recurrent bacterial infections, failure to thrive 
SLC39A7 (ZIP7) deficiency SLC39A7 AR 601416 Early-onset infections, blistering dermatosis, failure to thrive, thrombocytopenia 
Hoffman syndrome/TOP2B deficiency TOP2B AD 126431 Recurrent infections, facial dysmorphism, limb anomalies 
FNIP1 deficiency (6 patients) FNIP1 AR 619705 Early-onset recurrent infections, bronchiectasis, fibrosis, interstitial pneumonia; neutropenia (severe or intermittent); Crohn’s disease (one patient); congenital heart defects, muscular hypotonia; developmental delay 
PU1 deficiency SPI1 AD 619707 Sinopulmonary infections with encapsulated bacteria, viral infections 
PAX5 deficiency (n = 1) PAX5 AR   Early B-cell developmental block, B cell strongly decreased, transitional and naïve mature B cells expressed lower CD19 and IgD—natural effector and memory B cells, as well as plasmablasts, were absent in the blood of the patient; a-/hypo-gammaglobulinemia, recurrent infections, autism spectrum disorder (ASD), and sensorimotor and cognitive defects 
2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID phenotype 
Common variable immune deficiency with no gene defect specified (CVID) Unknown Variable NA Low IgG and IgA and/or IgM Clinical phenotypes vary most have recurrent infections; some have polyclonal lymphoproliferation, autoimmune cytopenias, and/or granulomatous disease 
Activated p110δ syndrome (APDS) PIK3CD GOF AD 615513 (APDS1) Normal/increased IgM, reduced IgG and IgA Severe bacterial infections, reduced memory B cells, and increased transitional B cells, EBV ± CMV viremia, lymphadenopathy/splenomegaly, autoimmunity, lymphoproliferation, lymphoma 
PIK3R1 AD 616005 (APDS2) Severe bacterial infections, reduced memory B cells, and increased transitional B cells, lymphadenopathy/splenomegaly, lymphoproliferation, lymphoma; developmental delay 
PTEN deficiency (LOF) PTEN AD 158350 Normal/decreased Recurrent infections, lymphoproliferation, autoimmunity; developmental delay 
CD19 deficiency CD19 AR 107265 Low IgG and IgA and/or IgM Recurrent infections, may have glomerulonephritis (CD81 mutation abolishes the expression of CD19, thereby phenocopying CD19 mutations) 
CD81 deficiency CD81 AR 186845 Low IgG, low or normal IgA and IgM 
CD20 deficiency MS4A1(CD20) AR 112210 Low IgG, normal or elevated IgM and IgA Recurrent infections 
CD21 deficiency CR2 (CD21) AR 120650 Low IgG, impaired anti-pneumococcal response Recurrent infections 
TACI deficiencya TNFRSF13B AR or AD 604907 Low IgG and IgA and/or IgM Variable clinical expression and penetrance for monoallelic variants 
BAFF receptor deficiency TNFRSF13C AR 606269 Low IgG and IgM Variable clinical expression 
TWEAK deficiency TNFSF12 AD 602695 Low IgM and IgA, lack of anti-pneumococcal antibody Pneumonia, bacterial infections, warts, thrombocytopenia, neutropenia 
TRNT1 deficiency TRNT1 AR 612907 B-cell deficiency and hypogammaglobulinemia Congenital sideroblastic anemia, deafness, developmental delay 
NFKB1 deficiency NFKB1 AD 164011 Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells Recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia, and autoimmune thyroiditis 
NFKB2 deficiency NFKB2 AD 615577 Low serum IgG, IgA, and IgM; low B-cell numbers Recurrent sinopulmonary infections, alopecia, and endocrinopathies 
IKAROS deficiency IKZF1 AD (haploinsufficiency) 603023 Low IgG, IgA, IgM, low or normal B cells; B cells and Ig levels reduce with age Decreased pro-B cells, recurrent sinopulmonary infections; increased risk of ALL, autoimmunity, CVID phenotype 
IRF2BP2 deficiency IRF2BP2 AD 615332 Hypogammaglobulinemia, absent IgA Recurrent infections, possible autoimmunity and inflammatory disease 
ATP6AP1 deficiency ATP6AP1 XL 300972 Variable immunoglobulin findings Hepatopathy, leukopenia, low copper 
ARHGEF1 deficiency ARHGEF1 AR 618459 Hypogammaglobulinemia; lack of antibody Recurrent infections, bronchiectasis 
SH3KBP1 (CIN85) deficiency SH3KBP1 XL 300310 IgM, IgG deficiency; loss of antibody Severe bacterial infections 
SEC61A1 deficiency SEC61A1 AD 609213 Hypogammaglobulinemia Severe recurrent respiratory tract infections 
RAC2 deficiency RAC2 AR 602049 Low IgG, IgA, IgM, low or normal B cells; reduced Ab responses following vaccination Recurrent sinopulmonary infections, selective IgA deficiency; poststreptococcal glomerulonephritis; urticaria 
Mannosyl-oligosaccharide glucosidase deficiency MOGS AR 601336 Low IgG, IgA, IgM, increased B cells; poor Ab responses following vaccination Bacterial and viral infections; severe neurological disease; also known as congenital disorder of glycosylation type IIb (CDG-IIb) 
PIK3CG deficiency PIK3CG AR 619802 Reduced memory B cells, hypogammaglobulinemia Recurrent infections, cytopenia/lymphopenia, eosinophilia, splenomegaly, lymphadenopathy, HLH-like 
BOB1 deficiency POU2AF1 AR NA Reduced memory B cells, agammaglobulinemia Recurrent respiratory infections, possible chronic viral infection of CNS with progressive tetraparesis 
KARS1 deficiency KARS1 AR 619147 Impaired B-cell metabolism (decreased mitochondrial numbers and activity). B-cell lymphopenia, hypogammaglobulinemia, impaired vaccine responses Severe developmental delay, sensorineural deafness, acute disseminated encephalomyelitis, central and peripheral nervous system impairment, heart and liver disease. Recurrent/severe infections 
PI4KA deficiency PI4KA AR 619708 Reduced total B cells, few memory B cells, hypogammaglobulinemia Recurrent infections; autoimmune/autoinflammatory, neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus with polymicrogyria, cerebellar hypoplasia, arthrogryposis), and gastrointestinal (inflammatory bowel disease, multiple intestinal atresia) manifestations 
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper-IgM 
AID deficiency AICDA AR 605258 IgG and IgA decreased, IgM increased; normal memory B cells but lacking somatic hypermutation Bacterial infections, enlarged lymph nodes and germinal centers; autoimmunity 
AD NA IgG absent or decreased, IgA undetected, IgM increased; normal memory B cells with intact somatic hypermutation Bacterial infections, enlarged lymph nodes and germinal centers. Variants uniquely localize to the nuclear export signal 
UNG deficiency UNG AR 191525 IgG and IgA decreased, IgM increased Enlarged lymph nodes and germinal centers 
INO80 deficiency INO80 AR 610169 IgG and IgA decreased, IgM increased Severe bacterial infections 
MSH6 deficiency MSH6 AR 600678 Variable IgG, defects, increased IgM in some, normal B cells, low switched memory B cells, Ig class switch recombination and somatic hypermutation defects Family or personal history of cancer 
CTNNBL1 deficiency CTNNBL1 AR 619846 Reduced memory B cells, Ig class switch recombination and somatic hypermutation defects, progressive hypogammaglobulinemia CVID, autoimmune cytopenias, recurrent infections, hyperplastic germinal centers 
APRIL deficiency TNFSF13 AR NA Normal total B-cell counts, reduced memory B cells, hypogammaglobulinemia CVID, chronic but mild infections, alopecia areata 
4. Isotype, light chain, or functional deficiencies with generally normal numbers of B cells 
Ig heavy chain mutations and deletions Mutation or chromosomal deletion at 14q32 AR  One or more IgG and/or IgA subclasses, as well as IgE, may be absent May be asymptomatic 
Kappa chain deficiency IGKC AR 147200 All immunoglobulins have lambda light chain Asymptomatic 
Isolated IgG subclass deficiency Unknown ND  Reduction in one or more IgG subclass Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections 
IgG subclass deficiency with IgA deficiency Unknown ND  Reduced IgA with a decrease in one or more IgG subclass Recurrent bacterial infections
May be asymptomatic 
Selective IgA deficiency Unknown ND  Absent IgA with other isotypes normal, normal subclasses, and specific antibodies May be asymptomatic
Bacterial infections, autoimmunity mildly increased 
Specific antibody deficiency with normal Ig levels and normal B cells Unknown ND  Normal Reduced ability to produce antibodies to specific antigens 
Transient hypogammaglobulinemia of infancy Unknown ND  IgG and IgA decreased Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections 
CARD11 GOF CARD11 AD GOF 616452 Polyclonal B-cell lymphocytosis due to constitutive NF-κB activation Splenomegaly, lymphadenopathy, poor vaccine response 
Selective IgM deficiency Unknown ND  Absent serum IgM Pneumococcal/bacterial 

EBV, Epstein-Barr virus; COPD, chronic obstructive pulmonary disease; ND, not determined; CNS, central nervous system; VODI, hepatic veno-occlusive disease with immunodeficiency; IBD, inflammatory bowel disease; CVID, common variable immunodeficiency; Ab, antibody.

CVID disorders include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells, as well as hypogammaglobulinemia. Identification of causal variants can assist in defining treatment. In addition to monogenic causes on this table, a small minority of patients with XLP (Table 4), WHIM syndrome (Table 6), ICF (Table 2), VODI (Table 2), thymoma with immunodeficiency (Good syndrome), or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia, and normal or reduced numbers of B cells.

Total number of mutant genes in Table 3: 48.

New IEIs: 3, PAX5, KARS1, and PI4K4 (48, 49, 50).

a

Heterozygous variants in TNFRSF13B have been detected in healthy individuals; thus, such variants are likely to be disease-modifying rather than disease-causing.

View large
Table 4.

Diseases of immune dysregulation

DiseaseGenetic defectInheritanceOMIMCirculating T cellsCirculating B cellsFunctional defectAssociated features
1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes 
Perforin deficiency (FHL2) PRF1 AR 170280 Increased activated T cells Normal Decreased to absent NK and CTL activities (cytotoxicity) Fever, HSM, HLH, cytopenias 
UNC13D/Munc13-4 deficiency (FHL3) UNC13D AR 608897 Increased activated T cells Normal Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) Fever, HSM, HLH, cytopenias 
Syntaxin 11 deficiency (FHL4) STX11 AR 605014 
STXBP2/Munc18-2 deficiency (FHL5) STXBP2 AR or AD 601717 
FAAP24 deficiency FAAP24 AR 610884 Increased activated T cells Normal Failure to kill autologous EBV transformed B cells. Normal NK cell function EBV-driven lymphoproliferative disease 
SLC7A7 deficiency SLC7A7 AR 222700 Normal Normal Hyperinflammatory response of macrophages
Normal NK cell function 		Lysinuric protein intolerance, bleeding tendency, alveolar proteinosis 
RHOG deficiency RHOG AR NA Normal Slightly reduced Impaired CTL and NK cell cytotoxicity HLH (hemophagocytosis, hepatosplenomegaly, fever, cytopenias, low hemoglobin, hypertriglyceridemia, elevated ferritin, sCD25) 
DPP9 deficiency DPP9 AR 620331 NA NA Aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Hyperinflammation with increased levels of IL-1β and IL-18 due to loss of NLRP1 repression. Normal NK cell function Increased susceptibility to infection (herpes, bronchitis, otitis media) pancytopenia (petechiae), recurrent fever, skin pigmentation abnormalities. Poor growth (short stature, failure to thrive) 
2. FHL syndromes with hypopigmentation 
Chediak–Higashi syndrome LYST AR 606897 Increased activated T cells Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, recurrent infections, fever, HSM, HLH, giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction 
Griscelli syndrome, type 2 RAB27A AR 603868 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, fever, HSM, HLH, cytopenias 
Hermansky–Pudlak syndrome, type 2 AP3B1 AR 603401 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, recurrent infections, pulmonary fibrosis, increased bleeding, neutropenia, HLH 
Hermansky–Pudlak syndrome, type 10 AP3D1 AR 617050 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss, and neurodevelopmental delay 
CEBPE multimorphic CEBPE AR GOF 260570 Mild reduction Not done Autoinflammasome activation/↑ IFN gene expression, altered chromatin occupancy of mutant CEBPE, and transcriptional changes Recurrent abdominal pain, aseptic fever, systemic inflammation; abscesses, ulceration, infections; mild bleeding diathesis 
3. Regulatory T-cell defects 
IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked FOXP3 XL 300292 Normal Normal Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) Autoimmune enteropathy, early-onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema, elevated IgE and IgA 
CD25 deficiency IL2RA AR 147730 Normal to decreased Normal No CD4+C25+ cells with impaired function of Treg cells Lymphoproliferation, autoimmunity, impaired T-cell proliferation in vitro 
CD122 deficiency IL2RB AR 618495 Increased memory CD8 T cells, decreased Tregs Increased memory B cells Diminished IL-2Rβ expression, dysregulated signaling in response to IL-2/IL-15; increased immature NK cells Lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, dermatitis, enteropathy, hypergammaglobulinemia, recurrent viral (EBV, CMV) infections 
CTLA4 haploinsufficiency (ALPS-V) CTLA4 AD 123890 Decreased Decreased Impaired function of Tregs Autoimmune cytopenias, enteropathy, interstitial lung disease, extralymphoid lymphocytic infiltration, recurrent infections 
LRBA deficiency LRBA AR 606453 Normal or decreased CD4 numbers; T-cell dysregulation Low or normal numbers of B cells Reduced IgG and IgA in most Recurrent infections, inflammatory bowel disease, autoimmunity 
DEF6 deficiency DEF6 AR 610094 Mild CD4 and CD8 lymphopenia Low or normal numbers of B cells Impaired Treg function Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections 
NBEAL2 deficiency NBEAL2 AR 139090 Low CTLA-4 expression in effector T cells, normal regulatory T cells   Gray platelet syndrome (macrothrombocytopenia, α-granule–deficient platelets, bleeding disorders), splenomegaly, and progression to myelofibrosis. Autoimmune lymphoproliferative syndrome, EBV reactivation, MAS 
STAT3 GOF STAT3 AD GOF 102582 Decreased Decreased Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation, and autoimmunity. Decreased Tregs and impaired function Lymphoproliferation, solid organ autoimmunity, recurrent infections 
BACH2 deficiency BACH2 AD 605394 Progressive T-cell lymphopenia Impaired memory B-cell development Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections 
FERMT1 deficiency FERMT1 AR 173650 Normal Normal Intracellular accumulation of IgG, IgM, IgA, and C3 in colloid bodies under the basement membrane Dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling 
IKAROS GOF IKZF1 AD GOF NA Normal Normal/mild decrease Increased binding of mutant IKAROS to DNA/target genes Multiple autoimmune features (diabetes, colitis, thyroiditis), allergy, lymphoproliferation, plasma cell expansion (IgG4+), Evans syndrome, recurrent infections 
4. Autoimmunity with or without lymphoproliferation 
APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy AIRE AR or AD 240300 Normal Normal AIRE serves as a checkpoint in the thymus for negative selection of autoreactive T cells and for generation of Tregs Autoimmunity: hypoparathyroidism, hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities; dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia; chronic mucocutaneous candidiasis 
ITCH deficiency ITCH AR 606409 Not assessed Not assessed Itch deficiency may cause immune dysregulation by affecting both anergy induction in autoreactive effector T cells and generation of Tregs Early-onset chronic lung disease (interstitial pneumonitis), autoimmunity (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis), failure to thrive, developmental delay, dysmorphic facial features 
Tripeptidyl peptidase II deficiency TPP2 AR 190470 Decreased Decreased TPP2 deficiency results in premature immunosenescence and immune dysregulation Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections 
JAK1 GOF JAK1 AD GOF 147795 Not assessed Not assessed Hyperactive JAK1 HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections 
Prolidase deficiency PEPD AR 613230 Normal Normal Peptidase D Autoantibodies common, chronic skin ulcers, eczema, infections 
SOCS1 haploinsufficiency SOCS1 AD 619375 Decreased Reduced switched memory B cells ↑pSTAT1, ↑ type I/II IFN signature Early-onset severe multisystemic autoimmunity, neutropenia, lymphopenia, ITP, AIHA, SLE, GN, hepatosplenomegaly, psoriasis, arthritis, thyroiditis, hepatitis; recurrent bacterial infections. Incomplete penetrance 
PD-1 deficiency PDCD1 AR 621004 Mostly intact expansion of CD4−CD8− double-negative (DN) αβ cells Normal Lack of PD-1 on patient PBMCs, reduced IFN-γ production in response to mycobacterial stimuli Tuberculosis, autoimmunity (T1D, hypothyroidism, JIA), fatal pulmonary autoimmunity, hepatosplenomegaly. Decreased proportions of CD56bright NK, Vδ2+ γδ T, and MAIT cells 
PD-L1 deficiency CD274 AR NA Normal, higher CD38 and HLA-DR expression on CD4+and CD8+αβ T lymphocytes Impaired IFN-γ expression by PD-L1 deficiency leukocytes. Memory B cells and antibody responses can be impaired Reduced, not absent, PD-L1 expression, on patient PBMC Neonatal-onset autoimmunity including T1 diabetes. Reduced proportions of Vδ2+γδ T and NK lymphocytes, MAIT 
TLR7 monogenic lupus TLR7 AD GOF 301080 Normal Normal, increased IgD−CD27−B cells, age-associated B cells Enhanced TLR7 signaling drives aberrant survival of B-cell receptor–activated B cells Childhood-onset SLE with multiple autoantibodies (ANA, dsDNA, U1RNP, etc.), hypocomplementemia, malar rash, autoimmune cytopenia, arthralgias, and glomerulonephritis. One patient with optic neuritis and transverse myelitis 
UNC93B1 monogenic lupus UNC93B1 AD GOF NA Reduction of CD4+ T cells and expansion of CD8+ T cells Increased hyperreactive CD27highCD38high plasmablasts, increased CD27−IgD− B cells Disrupts TLR trafficking resulting in TLR-7 hyperactivation, aberrant recognition of self-nucleic acids, and increased type I IFN signaling Early-onset SLE or chilblain lupus with refractory autoimmune thrombocytopenia, autoimmune anemia, and erythematous rash, hepatosplenomegaly, glomerulonephritis, arthritis, and panniculitis + autoantibodies. Transient leukocytosis (neutrophilia and monocytosis) and lymphocytopenia. High levels of lupus-associated cytokines 
TRAF3 haploinsufficiency TRAF3 AD haploinsufficiency 614849 Low total CD3+ and CD4+ T cells with decreased naïve and increased central memory populations. Decreases proportions of naïve CD8+ T cells. Increased Treg and TFH cells Normal CD19+; with low class-switched memory B cells
B-cell lymphoproliferation. High IgG, normal to high IgM 		Increased alternative NF-κB signaling in B cells Lymphadenopathy and splenomegaly. B cell lymphoproliferation. Recurrent sinopulmonary infections with poor polysaccharide responses and bronchiectasis. Immune dysregulation syndrome with autoimmunity and systemic inflammation: Sjögren’s syndrome with positive autoantibodies, vasculitis, glomerulonephritis, autoimmune thyroid disease, and systemic juvenile arthritis. Enteropathy. Multiple autoantibodies.
Atopic disease, dermatitis, allergies with high IgE in one patient 
CBLB deficiency CBLB AR 620430 Normal counts, hyperproliferative Normal Resistance to Treg suppression and increased B-cell signaling Autoimmune polyendocrinopathy (thyroid and type I DM), autoimmune cytopenias (AIHA, ITP), vitiligo, fevers, and polyserositis. Multiple autoantibodies 
PLCG1 GOF disease PLCG1 AD 620514 Normal Normal Exacerbated NF-κB and type II interferon pathway in patient T cells. Hyperactivated NF-κB and type I interferon pathway in monocytes Cytopenias (AIHA, ITP). Multiple autoantibodies. Lymphadenopathies. May have low NK cells 
SH2B3 deficiency SH2B3 AR 605093 NA NA Increased phosphorylation of JAK2, STAT5, and STAT3 Hepatosplenomegaly or splenomegaly with thrombocytosis, neutrophilia, and bone marrow showing myeloid and megakaryocytic hyperplasia. Multi-organ autoimmunity: autoimmune hepatitis, thyroiditis, type I DM, and alopecia areata. Monogenic lupus 
NCKAP1L deficiency NCKAP1L AR 618982 Normal number, DNT can be high, central memory and TEMRA can be increased Increased B cells with increased naïve B-cell proportion Actinopathy. Hyperinflammation and cytokine overproduction (↑Th1), ↑ T-cell proliferation, cytoskeletal defects Immune dysregulation with immunodeficiency coupled with hyperinflammation, lymphoproliferation, and autoimmunity
Recurrent infections, bronchiectasis. Hepatosplenomegaly. Atopy. HLH in one patient. Anti-dsDNA Abs, fever, FTT 
ARPC5 deficiency ARPC5 AR 620565 Low-normal CD4+T-cell counts, low recent thymic emigrant CD4+T-cell counts, low naïve CD8+T cells, excess of memory and TEMRA cells Increased B-cell counts, high frequency of age-associated B cells Actinopathy, normal/high IgG, IgA, and IgM (Ig3 elevated in 1 pt) Recurrent and severe infections, severe early-onset autoimmunity, inflammation, and dysmorphisms. Increased NKT cells, neutrophilia 
NFAT1 deficiency NFATC2 AR 620232 Normal with increased exhaustion markers Normal counts increased naïve, transitional, decreased switched memory B cells Calcium–calcineurin signals drive cell activation, proliferation, and survival Joint contractures, osteochondromas, B-cell lymphoma. No recurrent infections or autoimmunity although there was increased IL-6 in patient chondrocytes
EBV-driven lymphoproliferation, hypogammaglobulinemia without osteochondromas may occur 
LACC1 deficiency LACC1 AR 618795 NA NA Impaired autophagy in macrophages Systemic juvenile arthritis or polyarticular juvenile arthritis 
IRE1α deficiency ERN1 AD NA Normal Normal Defect of IRE1α over XBP1 splicing resulting in breakdown of B-cell tolerance Familial autoimmunity including SLE, Sjögren’s syndrome idiopathic thrombocytopenic purpura, Hashimoto thyroiditis, and limited cutaneous sclerosis. Positive ANA, DNA SSA/SSB autoantibodies 
GIMAP6 deficiency GIMAP6 AR 616960 Transient lymphopenia, decreased naïve T cells with high Tem and TEMRA CD4+cells. Reduced T-cell proliferation and activation and defective autophagy Normal B cells. Elevated IgM and β2 microglobulin, reduced IgA and IgG levels Reduced NK cell cytotoxicity Lymphadenopathy and splenomegaly. Vasculitis of CNS, skin, and lungs with pulmonary hypertension. Recurrent infections (pneumonia) with bronchiectasis. Antiphospholipid and anticardiolipin autoantibodies. Autoimmune hemolytic anemia 
PTPN2 PTPN2 AD NA Normal numbers may have mild CD4 T-cell lymphopenia. Hyperproliferative T cells. May have increased Tregs Normal numbers with increased self-reactive B cells. Normal immunoglobulin levels Loss of negative regulation in cytokine pathway resulting in ↑ STAT phosphorylation and ↑ inflammatory cytokines Pediatric-onset systemic lupus or Evans syndrome with incomplete penetrance. Positive autoantibodies (ANA, β2GP1, anti-C1q, ANCA, anti-HLA I). Slightly elevated type I IFN signature. Some patients may have hepatitis and cholangitis. Some may present with recurrent infections and lymphoproliferation 
5. Immune dysregulation with colitis 
IL-10 deficiency IL10 AR 124092 Normal Normal No functional IL-10 secretion IBD, folliculitis, recurrent respiratory diseases, arthritis 
IL-10R deficiency IL10RA AR 146933 Normal Normal Leukocytes unresponsive to IL-10 IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma 
IL10RB AR 123889 Normal Normal Leukocytes unresponsive to IL-10, and IL-22, IL-26, IL-28A, IL-28B, and IL-29 
NFAT5 haploinsufficiency NFAT5 AD 604708 Normal Normal Decreased memory B cells and plasmablasts IBD, recurrent sinopulmonary infections 
TGFB1 deficiency TGFB1 AR 618213 Normal Normal Decreased T-cell proliferation in response to anti-CD3 IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy 
RIPK1 RIPK1 AR 618108 Reduced Normal/reduced Reduced activation of MAPK, NF-κB pathways Recurrent infections, early-onset IBD, progressive polyarthritis 
ELF4 deficiency ELF4 XL 301074 Normal Normal Hyperinflammatory macrophages Early-onset IBD/mucosal autoinflammation, fevers, ulcers, responded to IL-1, TNF, or IL-12p40 blockade 
DOCK11 deficiency DOCK11 XL 301109 Normal Decreased switched memory B cells and MZ-like B cells Abnormal actin cytoskeleton remodeling due to impaired CDC42 activity and STAT5 activation, Treg defect Severe early-onset autoimmunity affecting various organs, GI (IBD), skin, lung, joints, etc. Some with SLE or JIA diagnosis. Susceptibility to infections with hyperinflammatory response. Normocytic anemia, variable thrombocytopenia 
iRHOM deficiency RHBDF2 AR  Normal Normal Failure to generate mature and active ADAM17 preventing TNF cleavage. Impaired TNF secretion in T cells.
Low IL-18 		Recurrent sinopulmonary infections with pneumatoceles, eczema, hepatosplenomegaly, skin abscesses, high IgE. Hemorrhagic colitis 
6. Autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome) 
ALPS-FAS FAS/TNFRSF6 AD 134637 Increased TCR α/β+
CD4−CD8− double-negative (DN) T cells 		Normal, low memory B cells Apoptosis defect FAS-mediated Splenomegaly, adenopathies, autoimmune cytopenias, increased lymphoma risk, IgG and IgA normal or increased, elevated serum FasL, IL-10, vitamin B12 
AR 
ALPS-FASLG FASLG/TNFSF6** AD/AR 134638 Increased DN T cells Normal Apoptosis defect FASL-mediated Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated 
ALPS-Caspase 10 CASP10 AD 601762 Increased DN T cells Normal Defective lymphocyte apoptosis Adenopathies, splenomegaly, autoimmunity 
ALPS-Caspase 8 CASP8 AR 601763 Slightly increased DN T cells Normal Defective lymphocyte apoptosis and activation Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia 
FADD deficiency FADD AR 602457 Increased DN T cells Normal Defective lymphocyte apoptosis Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction 
7. Susceptibility to EBV and lymphoproliferative conditions 
SAP deficiency (XLP1) SH2D1A XL 300490 Normal or increased activated T cells Reduced memory B cells Reduced NK cell and CTL cytotoxic activity Clinical and immunologic features triggered by EBV infection: HLH,
lymphoproliferation, aplastic anaemia, lymphoma.
Hypogammaglobulinemia,
absent iNKT cells 
XIAP deficiency (XLP2) XIAP XL 300079 Normal or increased activated T cells; low/normal iNK T cells Normal or reduced memory B cells Increased T-cell susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD) EBV infection, splenomegaly, lymphoproliferation
HLH, colitis, IBD, hepatitis
Low iNKT cells 
CD27 deficiency CD27 AR 615122 Normal No memory B cells Hypogammaglobulinemia; poor Ab responses to some vaccines/infections Features triggered by EBV infection, HLH, aplastic anemia, low iNKT cells, B lymphoma 
CD70 deficiency CD70 AR 602840 Normal number, low Treg, poor activation and function Decreased memory B cells Hypogammaglobulinemia; poor Ab responses to some vaccines/infections EBV susceptibility, Hodgkin lymphoma; autoimmunity in some patients 
CTPS1 deficiency CTPS1 AR 615897 Normal to low, but reduced activation, proliferation Decreased memory B cells Normal/high IgG poor proliferation to antigen Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma 
CD137 deficiency (41BB) TNFRSF9 AR 602250 Normal Normal Low IgG, low IgA, poor responses to T cell–dependent and T cell–independent antigens, decreased T-cell proliferation, IFN-γ secretion, cytotoxicity EBV lymphoproliferation, B-cell lymphoma, chronic active EBV infection 
TNFSF9 (CD137L) deficiency (41BBL) TNFSF9 AR 620282 Normal counts, ↓ EBV-specific T-cell effector responses Normal CD137L was not upregulated on activated monocytes and DCs, EBV-infected B cells. B cells failed to trigger the expansion of EBV-specific
T cells, resulting in ↓ T-cell effector responses 		Disseminated EBV in B and CD8+T cells, smooth muscle tumors 
RASGRP1 deficiency RASGRP1 AR 603962 Poor activation, proliferation, motility. Reduced naïve T cells Poor activation, proliferation, motility Normal IgM, IgG, increased IgA Recurrent pneumonia, herpesvirus infections, EBV-associated lymphoma
Decreased NK cell function 
RLTPR deficiency CARMIL2 AR 610859 Normal number, high CD4, increased naïve CD4+ and CD8+, low Treg and MAIT, poor CD28-induced function Normal B-cell numbers, reduced memory B cells Normal to low, poor T-dependent antibody response Recurrent bacterial, fungal, and mycobacterial infections, viral warts, molluscum and EBV lymphoproliferative and other malignancy, atopy 
X-linked magnesium EBV and neoplasia (XMEN) MAGT1 XL 300853 Low CD4 Low recent thymic emigrant cells, inverted CD4/CD8 ratio, reduced MAIT cells, poor proliferation to CD3 Normal but decreased memory B cells Progressive hypogammaglobulinemia
Reduced NK cell and CTL cytotoxic activity due to the impaired expression of NKG2D 		EBV infection, lymphoma, viral infections, respiratory and GI infections
Glycosylation defects 
PRKCD deficiency PRKCD AR 615559 Normal Low memory B cells, high CD5 B cells Apoptotic defect in B cells Recurrent infections, EBV chronic infection, lymphoproliferation, SLE-like autoimmunity (nephrotic and antiphospholipid syndromes), low IgG 
TET2 deficiency TET2 AR 619126 Increased CD4−CD8− T cells Low memory B cells DNA hypermethylation, defective FAS-mediated apoptosis ALPS-like, recurrent viral infections, EBV viremia, lymphadenopathy, hepatosplenomegaly, autoimmunity, B lymphoma, FTT, developmental delay 
IL-27RA deficiency IL27RA AR  Normal Normal Phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells, impaired expansion of potent anti-EBV effector cytotoxic CD8+T cells Acute and severe primary EBV infection with a favorable outcome 
DiseaseGenetic defectInheritanceOMIMCirculating T cellsCirculating B cellsFunctional defectAssociated features
1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes 
Perforin deficiency (FHL2) PRF1 AR 170280 Increased activated T cells Normal Decreased to absent NK and CTL activities (cytotoxicity) Fever, HSM, HLH, cytopenias 
UNC13D/Munc13-4 deficiency (FHL3) UNC13D AR 608897 Increased activated T cells Normal Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) Fever, HSM, HLH, cytopenias 
Syntaxin 11 deficiency (FHL4) STX11 AR 605014 
STXBP2/Munc18-2 deficiency (FHL5) STXBP2 AR or AD 601717 
FAAP24 deficiency FAAP24 AR 610884 Increased activated T cells Normal Failure to kill autologous EBV transformed B cells. Normal NK cell function EBV-driven lymphoproliferative disease 
SLC7A7 deficiency SLC7A7 AR 222700 Normal Normal Hyperinflammatory response of macrophages
Normal NK cell function 		Lysinuric protein intolerance, bleeding tendency, alveolar proteinosis 
RHOG deficiency RHOG AR NA Normal Slightly reduced Impaired CTL and NK cell cytotoxicity HLH (hemophagocytosis, hepatosplenomegaly, fever, cytopenias, low hemoglobin, hypertriglyceridemia, elevated ferritin, sCD25) 
DPP9 deficiency DPP9 AR 620331 NA NA Aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Hyperinflammation with increased levels of IL-1β and IL-18 due to loss of NLRP1 repression. Normal NK cell function Increased susceptibility to infection (herpes, bronchitis, otitis media) pancytopenia (petechiae), recurrent fever, skin pigmentation abnormalities. Poor growth (short stature, failure to thrive) 
2. FHL syndromes with hypopigmentation 
Chediak–Higashi syndrome LYST AR 606897 Increased activated T cells Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, recurrent infections, fever, HSM, HLH, giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction 
Griscelli syndrome, type 2 RAB27A AR 603868 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, fever, HSM, HLH, cytopenias 
Hermansky–Pudlak syndrome, type 2 AP3B1 AR 603401 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, recurrent infections, pulmonary fibrosis, increased bleeding, neutropenia, HLH 
Hermansky–Pudlak syndrome, type 10 AP3D1 AR 617050 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss, and neurodevelopmental delay 
CEBPE multimorphic CEBPE AR GOF 260570 Mild reduction Not done Autoinflammasome activation/↑ IFN gene expression, altered chromatin occupancy of mutant CEBPE, and transcriptional changes Recurrent abdominal pain, aseptic fever, systemic inflammation; abscesses, ulceration, infections; mild bleeding diathesis 
3. Regulatory T-cell defects 
IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked FOXP3 XL 300292 Normal Normal Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) Autoimmune enteropathy, early-onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema, elevated IgE and IgA 
CD25 deficiency IL2RA AR 147730 Normal to decreased Normal No CD4+C25+ cells with impaired function of Treg cells Lymphoproliferation, autoimmunity, impaired T-cell proliferation in vitro 
CD122 deficiency IL2RB AR 618495 Increased memory CD8 T cells, decreased Tregs Increased memory B cells Diminished IL-2Rβ expression, dysregulated signaling in response to IL-2/IL-15; increased immature NK cells Lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, dermatitis, enteropathy, hypergammaglobulinemia, recurrent viral (EBV, CMV) infections 
CTLA4 haploinsufficiency (ALPS-V) CTLA4 AD 123890 Decreased Decreased Impaired function of Tregs Autoimmune cytopenias, enteropathy, interstitial lung disease, extralymphoid lymphocytic infiltration, recurrent infections 
LRBA deficiency LRBA AR 606453 Normal or decreased CD4 numbers; T-cell dysregulation Low or normal numbers of B cells Reduced IgG and IgA in most Recurrent infections, inflammatory bowel disease, autoimmunity 
DEF6 deficiency DEF6 AR 610094 Mild CD4 and CD8 lymphopenia Low or normal numbers of B cells Impaired Treg function Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections 
NBEAL2 deficiency NBEAL2 AR 139090 Low CTLA-4 expression in effector T cells, normal regulatory T cells   Gray platelet syndrome (macrothrombocytopenia, α-granule–deficient platelets, bleeding disorders), splenomegaly, and progression to myelofibrosis. Autoimmune lymphoproliferative syndrome, EBV reactivation, MAS 
STAT3 GOF STAT3 AD GOF 102582 Decreased Decreased Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation, and autoimmunity. Decreased Tregs and impaired function Lymphoproliferation, solid organ autoimmunity, recurrent infections 
BACH2 deficiency BACH2 AD 605394 Progressive T-cell lymphopenia Impaired memory B-cell development Haploinsufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections 
FERMT1 deficiency FERMT1 AR 173650 Normal Normal Intracellular accumulation of IgG, IgM, IgA, and C3 in colloid bodies under the basement membrane Dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling 
IKAROS GOF IKZF1 AD GOF NA Normal Normal/mild decrease Increased binding of mutant IKAROS to DNA/target genes Multiple autoimmune features (diabetes, colitis, thyroiditis), allergy, lymphoproliferation, plasma cell expansion (IgG4+), Evans syndrome, recurrent infections 
4. Autoimmunity with or without lymphoproliferation 
APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy AIRE AR or AD 240300 Normal Normal AIRE serves as a checkpoint in the thymus for negative selection of autoreactive T cells and for generation of Tregs Autoimmunity: hypoparathyroidism, hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities; dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia; chronic mucocutaneous candidiasis 
ITCH deficiency ITCH AR 606409 Not assessed Not assessed Itch deficiency may cause immune dysregulation by affecting both anergy induction in autoreactive effector T cells and generation of Tregs Early-onset chronic lung disease (interstitial pneumonitis), autoimmunity (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis), failure to thrive, developmental delay, dysmorphic facial features 
Tripeptidyl peptidase II deficiency TPP2 AR 190470 Decreased Decreased TPP2 deficiency results in premature immunosenescence and immune dysregulation Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections 
JAK1 GOF JAK1 AD GOF 147795 Not assessed Not assessed Hyperactive JAK1 HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections 
Prolidase deficiency PEPD AR 613230 Normal Normal Peptidase D Autoantibodies common, chronic skin ulcers, eczema, infections 
SOCS1 haploinsufficiency SOCS1 AD 619375 Decreased Reduced switched memory B cells ↑pSTAT1, ↑ type I/II IFN signature Early-onset severe multisystemic autoimmunity, neutropenia, lymphopenia, ITP, AIHA, SLE, GN, hepatosplenomegaly, psoriasis, arthritis, thyroiditis, hepatitis; recurrent bacterial infections. Incomplete penetrance 
PD-1 deficiency PDCD1 AR 621004 Mostly intact expansion of CD4−CD8− double-negative (DN) αβ cells Normal Lack of PD-1 on patient PBMCs, reduced IFN-γ production in response to mycobacterial stimuli Tuberculosis, autoimmunity (T1D, hypothyroidism, JIA), fatal pulmonary autoimmunity, hepatosplenomegaly. Decreased proportions of CD56bright NK, Vδ2+ γδ T, and MAIT cells 
PD-L1 deficiency CD274 AR NA Normal, higher CD38 and HLA-DR expression on CD4+and CD8+αβ T lymphocytes Impaired IFN-γ expression by PD-L1 deficiency leukocytes. Memory B cells and antibody responses can be impaired Reduced, not absent, PD-L1 expression, on patient PBMC Neonatal-onset autoimmunity including T1 diabetes. Reduced proportions of Vδ2+γδ T and NK lymphocytes, MAIT 
TLR7 monogenic lupus TLR7 AD GOF 301080 Normal Normal, increased IgD−CD27−B cells, age-associated B cells Enhanced TLR7 signaling drives aberrant survival of B-cell receptor–activated B cells Childhood-onset SLE with multiple autoantibodies (ANA, dsDNA, U1RNP, etc.), hypocomplementemia, malar rash, autoimmune cytopenia, arthralgias, and glomerulonephritis. One patient with optic neuritis and transverse myelitis 
UNC93B1 monogenic lupus UNC93B1 AD GOF NA Reduction of CD4+ T cells and expansion of CD8+ T cells Increased hyperreactive CD27highCD38high plasmablasts, increased CD27−IgD− B cells Disrupts TLR trafficking resulting in TLR-7 hyperactivation, aberrant recognition of self-nucleic acids, and increased type I IFN signaling Early-onset SLE or chilblain lupus with refractory autoimmune thrombocytopenia, autoimmune anemia, and erythematous rash, hepatosplenomegaly, glomerulonephritis, arthritis, and panniculitis + autoantibodies. Transient leukocytosis (neutrophilia and monocytosis) and lymphocytopenia. High levels of lupus-associated cytokines 
TRAF3 haploinsufficiency TRAF3 AD haploinsufficiency 614849 Low total CD3+ and CD4+ T cells with decreased naïve and increased central memory populations. Decreases proportions of naïve CD8+ T cells. Increased Treg and TFH cells Normal CD19+; with low class-switched memory B cells
B-cell lymphoproliferation. High IgG, normal to high IgM 		Increased alternative NF-κB signaling in B cells Lymphadenopathy and splenomegaly. B cell lymphoproliferation. Recurrent sinopulmonary infections with poor polysaccharide responses and bronchiectasis. Immune dysregulation syndrome with autoimmunity and systemic inflammation: Sjögren’s syndrome with positive autoantibodies, vasculitis, glomerulonephritis, autoimmune thyroid disease, and systemic juvenile arthritis. Enteropathy. Multiple autoantibodies.
Atopic disease, dermatitis, allergies with high IgE in one patient 
CBLB deficiency CBLB AR 620430 Normal counts, hyperproliferative Normal Resistance to Treg suppression and increased B-cell signaling Autoimmune polyendocrinopathy (thyroid and type I DM), autoimmune cytopenias (AIHA, ITP), vitiligo, fevers, and polyserositis. Multiple autoantibodies 
PLCG1 GOF disease PLCG1 AD 620514 Normal Normal Exacerbated NF-κB and type II interferon pathway in patient T cells. Hyperactivated NF-κB and type I interferon pathway in monocytes Cytopenias (AIHA, ITP). Multiple autoantibodies. Lymphadenopathies. May have low NK cells 
SH2B3 deficiency SH2B3 AR 605093 NA NA Increased phosphorylation of JAK2, STAT5, and STAT3 Hepatosplenomegaly or splenomegaly with thrombocytosis, neutrophilia, and bone marrow showing myeloid and megakaryocytic hyperplasia. Multi-organ autoimmunity: autoimmune hepatitis, thyroiditis, type I DM, and alopecia areata. Monogenic lupus 
NCKAP1L deficiency NCKAP1L AR 618982 Normal number, DNT can be high, central memory and TEMRA can be increased Increased B cells with increased naïve B-cell proportion Actinopathy. Hyperinflammation and cytokine overproduction (↑Th1), ↑ T-cell proliferation, cytoskeletal defects Immune dysregulation with immunodeficiency coupled with hyperinflammation, lymphoproliferation, and autoimmunity
Recurrent infections, bronchiectasis. Hepatosplenomegaly. Atopy. HLH in one patient. Anti-dsDNA Abs, fever, FTT 
ARPC5 deficiency ARPC5 AR 620565 Low-normal CD4+T-cell counts, low recent thymic emigrant CD4+T-cell counts, low naïve CD8+T cells, excess of memory and TEMRA cells Increased B-cell counts, high frequency of age-associated B cells Actinopathy, normal/high IgG, IgA, and IgM (Ig3 elevated in 1 pt) Recurrent and severe infections, severe early-onset autoimmunity, inflammation, and dysmorphisms. Increased NKT cells, neutrophilia 
NFAT1 deficiency NFATC2 AR 620232 Normal with increased exhaustion markers Normal counts increased naïve, transitional, decreased switched memory B cells Calcium–calcineurin signals drive cell activation, proliferation, and survival Joint contractures, osteochondromas, B-cell lymphoma. No recurrent infections or autoimmunity although there was increased IL-6 in patient chondrocytes
EBV-driven lymphoproliferation, hypogammaglobulinemia without osteochondromas may occur 
LACC1 deficiency LACC1 AR 618795 NA NA Impaired autophagy in macrophages Systemic juvenile arthritis or polyarticular juvenile arthritis 
IRE1α deficiency ERN1 AD NA Normal Normal Defect of IRE1α over XBP1 splicing resulting in breakdown of B-cell tolerance Familial autoimmunity including SLE, Sjögren’s syndrome idiopathic thrombocytopenic purpura, Hashimoto thyroiditis, and limited cutaneous sclerosis. Positive ANA, DNA SSA/SSB autoantibodies 
GIMAP6 deficiency GIMAP6 AR 616960 Transient lymphopenia, decreased naïve T cells with high Tem and TEMRA CD4+cells. Reduced T-cell proliferation and activation and defective autophagy Normal B cells. Elevated IgM and β2 microglobulin, reduced IgA and IgG levels Reduced NK cell cytotoxicity Lymphadenopathy and splenomegaly. Vasculitis of CNS, skin, and lungs with pulmonary hypertension. Recurrent infections (pneumonia) with bronchiectasis. Antiphospholipid and anticardiolipin autoantibodies. Autoimmune hemolytic anemia 
PTPN2 PTPN2 AD NA Normal numbers may have mild CD4 T-cell lymphopenia. Hyperproliferative T cells. May have increased Tregs Normal numbers with increased self-reactive B cells. Normal immunoglobulin levels Loss of negative regulation in cytokine pathway resulting in ↑ STAT phosphorylation and ↑ inflammatory cytokines Pediatric-onset systemic lupus or Evans syndrome with incomplete penetrance. Positive autoantibodies (ANA, β2GP1, anti-C1q, ANCA, anti-HLA I). Slightly elevated type I IFN signature. Some patients may have hepatitis and cholangitis. Some may present with recurrent infections and lymphoproliferation 
5. Immune dysregulation with colitis 
IL-10 deficiency IL10 AR 124092 Normal Normal No functional IL-10 secretion IBD, folliculitis, recurrent respiratory diseases, arthritis 
IL-10R deficiency IL10RA AR 146933 Normal Normal Leukocytes unresponsive to IL-10 IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma 
IL10RB AR 123889 Normal Normal Leukocytes unresponsive to IL-10, and IL-22, IL-26, IL-28A, IL-28B, and IL-29 
NFAT5 haploinsufficiency NFAT5 AD 604708 Normal Normal Decreased memory B cells and plasmablasts IBD, recurrent sinopulmonary infections 
TGFB1 deficiency TGFB1 AR 618213 Normal Normal Decreased T-cell proliferation in response to anti-CD3 IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy 
RIPK1 RIPK1 AR 618108 Reduced Normal/reduced Reduced activation of MAPK, NF-κB pathways Recurrent infections, early-onset IBD, progressive polyarthritis 
ELF4 deficiency ELF4 XL 301074 Normal Normal Hyperinflammatory macrophages Early-onset IBD/mucosal autoinflammation, fevers, ulcers, responded to IL-1, TNF, or IL-12p40 blockade 
DOCK11 deficiency DOCK11 XL 301109 Normal Decreased switched memory B cells and MZ-like B cells Abnormal actin cytoskeleton remodeling due to impaired CDC42 activity and STAT5 activation, Treg defect Severe early-onset autoimmunity affecting various organs, GI (IBD), skin, lung, joints, etc. Some with SLE or JIA diagnosis. Susceptibility to infections with hyperinflammatory response. Normocytic anemia, variable thrombocytopenia 
iRHOM deficiency RHBDF2 AR  Normal Normal Failure to generate mature and active ADAM17 preventing TNF cleavage. Impaired TNF secretion in T cells.
Low IL-18 		Recurrent sinopulmonary infections with pneumatoceles, eczema, hepatosplenomegaly, skin abscesses, high IgE. Hemorrhagic colitis 
6. Autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome) 
ALPS-FAS FAS/TNFRSF6 AD 134637 Increased TCR α/β+
CD4−CD8− double-negative (DN) T cells 		Normal, low memory B cells Apoptosis defect FAS-mediated Splenomegaly, adenopathies, autoimmune cytopenias, increased lymphoma risk, IgG and IgA normal or increased, elevated serum FasL, IL-10, vitamin B12 
AR 
ALPS-FASLG FASLG/TNFSF6** AD/AR 134638 Increased DN T cells Normal Apoptosis defect FASL-mediated Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated 
ALPS-Caspase 10 CASP10 AD 601762 Increased DN T cells Normal Defective lymphocyte apoptosis Adenopathies, splenomegaly, autoimmunity 
ALPS-Caspase 8 CASP8 AR 601763 Slightly increased DN T cells Normal Defective lymphocyte apoptosis and activation Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia 
FADD deficiency FADD AR 602457 Increased DN T cells Normal Defective lymphocyte apoptosis Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction 
7. Susceptibility to EBV and lymphoproliferative conditions 
SAP deficiency (XLP1) SH2D1A XL 300490 Normal or increased activated T cells Reduced memory B cells Reduced NK cell and CTL cytotoxic activity Clinical and immunologic features triggered by EBV infection: HLH,
lymphoproliferation, aplastic anaemia, lymphoma.
Hypogammaglobulinemia,
absent iNKT cells 
XIAP deficiency (XLP2) XIAP XL 300079 Normal or increased activated T cells; low/normal iNK T cells Normal or reduced memory B cells Increased T-cell susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD) EBV infection, splenomegaly, lymphoproliferation
HLH, colitis, IBD, hepatitis
Low iNKT cells 
CD27 deficiency CD27 AR 615122 Normal No memory B cells Hypogammaglobulinemia; poor Ab responses to some vaccines/infections Features triggered by EBV infection, HLH, aplastic anemia, low iNKT cells, B lymphoma 
CD70 deficiency CD70 AR 602840 Normal number, low Treg, poor activation and function Decreased memory B cells Hypogammaglobulinemia; poor Ab responses to some vaccines/infections EBV susceptibility, Hodgkin lymphoma; autoimmunity in some patients 
CTPS1 deficiency CTPS1 AR 615897 Normal to low, but reduced activation, proliferation Decreased memory B cells Normal/high IgG poor proliferation to antigen Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma 
CD137 deficiency (41BB) TNFRSF9 AR 602250 Normal Normal Low IgG, low IgA, poor responses to T cell–dependent and T cell–independent antigens, decreased T-cell proliferation, IFN-γ secretion, cytotoxicity EBV lymphoproliferation, B-cell lymphoma, chronic active EBV infection 
TNFSF9 (CD137L) deficiency (41BBL) TNFSF9 AR 620282 Normal counts, ↓ EBV-specific T-cell effector responses Normal CD137L was not upregulated on activated monocytes and DCs, EBV-infected B cells. B cells failed to trigger the expansion of EBV-specific
T cells, resulting in ↓ T-cell effector responses 		Disseminated EBV in B and CD8+T cells, smooth muscle tumors 
RASGRP1 deficiency RASGRP1 AR 603962 Poor activation, proliferation, motility. Reduced naïve T cells Poor activation, proliferation, motility Normal IgM, IgG, increased IgA Recurrent pneumonia, herpesvirus infections, EBV-associated lymphoma
Decreased NK cell function 
RLTPR deficiency CARMIL2 AR 610859 Normal number, high CD4, increased naïve CD4+ and CD8+, low Treg and MAIT, poor CD28-induced function Normal B-cell numbers, reduced memory B cells Normal to low, poor T-dependent antibody response Recurrent bacterial, fungal, and mycobacterial infections, viral warts, molluscum and EBV lymphoproliferative and other malignancy, atopy 
X-linked magnesium EBV and neoplasia (XMEN) MAGT1 XL 300853 Low CD4 Low recent thymic emigrant cells, inverted CD4/CD8 ratio, reduced MAIT cells, poor proliferation to CD3 Normal but decreased memory B cells Progressive hypogammaglobulinemia
Reduced NK cell and CTL cytotoxic activity due to the impaired expression of NKG2D 		EBV infection, lymphoma, viral infections, respiratory and GI infections
Glycosylation defects 
PRKCD deficiency PRKCD AR 615559 Normal Low memory B cells, high CD5 B cells Apoptotic defect in B cells Recurrent infections, EBV chronic infection, lymphoproliferation, SLE-like autoimmunity (nephrotic and antiphospholipid syndromes), low IgG 
TET2 deficiency TET2 AR 619126 Increased CD4−CD8− T cells Low memory B cells DNA hypermethylation, defective FAS-mediated apoptosis ALPS-like, recurrent viral infections, EBV viremia, lymphadenopathy, hepatosplenomegaly, autoimmunity, B lymphoma, FTT, developmental delay 
IL-27RA deficiency IL27RA AR  Normal Normal Phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells, impaired expansion of potent anti-EBV effector cytotoxic CD8+T cells Acute and severe primary EBV infection with a favorable outcome 

FHL, familial hemophagocytic lymphohistiocytosis; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; DN, double-negative; SLE, systemic lupus erythematous; IBD, inflammatory bowel disease; ALPS, autoimmune lymphoproliferative syndrome; CNS, central nervous system; Ab, antibody.

Total number of defects in Table 4: 72.

New IEIs: 19, CD274 (PDL1), TLR7 GOF, UNC93B1 GOF, TRAF3, CBLB, PLCG1, SH2B3, ARPC5, NFATC2, DOCK11, RHBDF2, LACC1, ERN1, NBEAL2, IL27RA, TNFSF9, DPP9, GIMAP6, and PTPN2 (23, 25, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72).

** depicts that somatic mutations mimicking the germline disorder have been described for this gene.

View large
Table 5.

Congenital defects of phagocyte number or function

DiseaseGenetic defectInheritanceOMIMAffected cellsAffected functionAssociated features
1. Congenital neutropenias 
Elastase deficiency (severe congenital neutropenia [SCN] 1) ELANE AD 130130 N Myeloid differentiation Susceptibility to MDS/leukemia
Severe congenital neutropenia or cyclic neutropenia 
GFI 1 deficiency (SCN2) GFI1 AD 600871 N Myeloid differentiation B/T lymphopenia 
HAX1 deficiency (Kostmann disease) (SCN3) HAX1 AR 605998 N Myeloid differentiation Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia 
G6PC3 deficiency (SCN4) G6PC3 AR 611045 N Myeloid differentiation, chemotaxis
O2− production 		Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasia of trunks and limbs 
VPS45 deficiency (SCN5) VPS45 AR 610035 N Myeloid differentiation, migration Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly 
Glycogen storage disease type 1b SLC37A4/G6PT1 AR 602671 N + M Myeloid differentiation, chemotaxis,
O2− production 		Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly 
X-linked neutropenia/myelodysplasia WAS XL GOF 300299 N Differentiation, mitosis. Results from GOF mutations in GTPase binding domain of WASP Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies 
P14/LAMTOR2 deficiency LAMTOR2 AR 610389 N + M Endosomal biogenesis Neutropenia
Hypogammaglobulinemia CD8− cytotoxicity, partial albinism, growth failure 
Barth syndrome (3-methylglutaconic aciduria type II) TAZ XL 300394 N+L
Mel 		Mitochondrial function Cardiomyopathy, myopathy, growth retardation, neutropenia 
Cohen syndrome VPS13B AR 607817 N Myeloid differentiation Dysmorphism, mental retardation, obesity, deafness, neutropenia 
Clericuzio syndrome (poikiloderma with neutropenia) USB1 AR 613276 N Myeloid differentiation Retinopathy, developmental delay, facial dysmorphisms, poikiloderma 
JAGN1 deficiency JAGN1 AR 616012 N Myeloid differentiation Myeloid maturation arrest, osteopenia 
3-Methylglutaconic aciduria CLPB AD/AR 616254 N Myeloid differentiation
Mitochondrial protein 		Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR 
G-CSF receptor deficiency CSF3R AR 138971 N Stress granulopoiesis disturbed  
SMARCD2 deficiency SMARCD2 AR 601736 N Chromatin remodeling, myeloid differentiation, and neutrophil functional defect Neutropenia, developmental aberrations, bones, hematopoietic stem cells, myelodysplasia 
CEBPE deficiency CEBPE AR 245480 N Terminal maturation and global dysfunction Neutropenia, neutrophils with bilobed nuclei, poor chemotaxis 
Shwachman–Diamond syndrome SBDS AR 607444 N Neutrophil maturation, chemotaxis, ribosomal biogenesis Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia 
DNAJC21 AR 617052 N + HSC Pancytopenia, exocrine pancreatic insufficiency 
EFL1 AR 617941 N + HSC 
HYOU1 deficiency HYOU1 AR 601746 N Unfolded protein response Hypoglycemia, inflammatory complications 
SRP54 deficiency SRP54 AD 604857 N Protein translocation to ER, myeloid differentiation, and neutrophil functional defect Neutropenia, exocrine pancreatic insufficiency 
CXCR2 deficiency CXCR2 AR 619407 N Reduced expression of CXCR2 on patient cells, impaired responses to CXCL8 Profound neutropenia, myelokathexis, recurrent gingivitis, oral ulcers, hypergammaglobulinemia 
DBF4 deficiency DBF4 AR NA N Disturbed cell cycle Neurocognitive developmental aberrations 
SRP19/SRPRA deficiency SRP19 AR NA N Alterations in neutrophil granulocyte development with reduction in electron-dense granules Exocrine pancreatic insufficiency, growth insufficiency, recurrent pulmonary infections with bronchiectasis, congenital neutropenia 
SRPRA 
2. Defects of motility 
Leukocyte adhesion deficiency type 1 (LAD1) ITGB2 AR 600065 N + M +
L + NK 		Adherence, chemotaxis, endocytosis, T/NK cytotoxicity Delayed cord separation, skin ulcers, periodontitis, leukocytosis 
Leukocyte adhesion deficiency type 2 (LAD2) SLC35C1 AR 605881 N + M Rolling, chemotaxis Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay 
Leukocyte adhesion deficiency type 3 (LAD3) FERMT3 AR 607901 N + M +
L + NK 		Adherence, chemotaxis LAD type 1 plus bleeding tendency 
Rac2 deficiency RAC2 AD LOF 608203 N Adherence, chemotaxis
O2− production 		Poor wound healing, leukocytosis 
β-Actin deficiency ACTB AD 102630 N + M Motility Mental retardation, short stature 
Localized juvenile periodontitis FPR1 AR 136537 N Formyl peptide–induced chemotaxis Periodontitis only 
Papillon–Lefèvre syndrome CTSC AR 602365 N + M Chemotaxis Periodontitis, palmoplantar hyperkeratosis in some patients 
WDR1 deficiency WDR1 AR 604734 N Spreading, survival, chemotaxis Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nucleus herniate 
Cystic fibrosis CFTR AR 602421 M only Chemotaxis Respiratory infections, pancreatic insufficiency, elevated sweat chloride 
Neutropenia with combined immune deficiency due to MKL1 deficiency MAP3K9/MKL1 AR 606078 N + M +L + NK Impaired expression of cytoskeletal genes Mild thrombocytopenia 
CCR2 CCR2 AR 219600 M Impaired CCL2-dependent monocyte migration to the lungs and infected tissues Pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including BCG disease 
3. Defects of respiratory burst 
X-linked chronic granulomatous disease (CGD), gp91phox CYBB XL 306400 N + M Killing (faulty O2− production) Infections, autoinflammatory phenotype, IBD
McLeod phenotype in patients with deletions extending into the contiguous Kell locus 
AR CGD CYBA AR 608508 Infections, autoinflammatory phenotype 
CYBC1 618334 
NCF1 608512 
NCF2 608515 
NCF4 613960 
G6PD deficiency class I G6PD XL 305900 N Reduced O2− production Infections 
4. Other nonlymphoid defects 
Pulmonary alveolar proteinosis CSF2RA XL (biallelic mutations in pseudoautosomal gene) 300770 Alveolar macrophages GM-CSF signaling Alveolar proteinosis 
CSF2RB AR 614370 
DiseaseGenetic defectInheritanceOMIMAffected cellsAffected functionAssociated features
1. Congenital neutropenias 
Elastase deficiency (severe congenital neutropenia [SCN] 1) ELANE AD 130130 N Myeloid differentiation Susceptibility to MDS/leukemia
Severe congenital neutropenia or cyclic neutropenia 
GFI 1 deficiency (SCN2) GFI1 AD 600871 N Myeloid differentiation B/T lymphopenia 
HAX1 deficiency (Kostmann disease) (SCN3) HAX1 AR 605998 N Myeloid differentiation Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia 
G6PC3 deficiency (SCN4) G6PC3 AR 611045 N Myeloid differentiation, chemotaxis
O2− production 		Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasia of trunks and limbs 
VPS45 deficiency (SCN5) VPS45 AR 610035 N Myeloid differentiation, migration Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly 
Glycogen storage disease type 1b SLC37A4/G6PT1 AR 602671 N + M Myeloid differentiation, chemotaxis,
O2− production 		Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly 
X-linked neutropenia/myelodysplasia WAS XL GOF 300299 N Differentiation, mitosis. Results from GOF mutations in GTPase binding domain of WASP Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies 
P14/LAMTOR2 deficiency LAMTOR2 AR 610389 N + M Endosomal biogenesis Neutropenia
Hypogammaglobulinemia CD8− cytotoxicity, partial albinism, growth failure 
Barth syndrome (3-methylglutaconic aciduria type II) TAZ XL 300394 N+L
Mel 		Mitochondrial function Cardiomyopathy, myopathy, growth retardation, neutropenia 
Cohen syndrome VPS13B AR 607817 N Myeloid differentiation Dysmorphism, mental retardation, obesity, deafness, neutropenia 
Clericuzio syndrome (poikiloderma with neutropenia) USB1 AR 613276 N Myeloid differentiation Retinopathy, developmental delay, facial dysmorphisms, poikiloderma 
JAGN1 deficiency JAGN1 AR 616012 N Myeloid differentiation Myeloid maturation arrest, osteopenia 
3-Methylglutaconic aciduria CLPB AD/AR 616254 N Myeloid differentiation
Mitochondrial protein 		Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR 
G-CSF receptor deficiency CSF3R AR 138971 N Stress granulopoiesis disturbed  
SMARCD2 deficiency SMARCD2 AR 601736 N Chromatin remodeling, myeloid differentiation, and neutrophil functional defect Neutropenia, developmental aberrations, bones, hematopoietic stem cells, myelodysplasia 
CEBPE deficiency CEBPE AR 245480 N Terminal maturation and global dysfunction Neutropenia, neutrophils with bilobed nuclei, poor chemotaxis 
Shwachman–Diamond syndrome SBDS AR 607444 N Neutrophil maturation, chemotaxis, ribosomal biogenesis Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia 
DNAJC21 AR 617052 N + HSC Pancytopenia, exocrine pancreatic insufficiency 
EFL1 AR 617941 N + HSC 
HYOU1 deficiency HYOU1 AR 601746 N Unfolded protein response Hypoglycemia, inflammatory complications 
SRP54 deficiency SRP54 AD 604857 N Protein translocation to ER, myeloid differentiation, and neutrophil functional defect Neutropenia, exocrine pancreatic insufficiency 
CXCR2 deficiency CXCR2 AR 619407 N Reduced expression of CXCR2 on patient cells, impaired responses to CXCL8 Profound neutropenia, myelokathexis, recurrent gingivitis, oral ulcers, hypergammaglobulinemia 
DBF4 deficiency DBF4 AR NA N Disturbed cell cycle Neurocognitive developmental aberrations 
SRP19/SRPRA deficiency SRP19 AR NA N Alterations in neutrophil granulocyte development with reduction in electron-dense granules Exocrine pancreatic insufficiency, growth insufficiency, recurrent pulmonary infections with bronchiectasis, congenital neutropenia 
SRPRA 
2. Defects of motility 
Leukocyte adhesion deficiency type 1 (LAD1) ITGB2 AR 600065 N + M +
L + NK 		Adherence, chemotaxis, endocytosis, T/NK cytotoxicity Delayed cord separation, skin ulcers, periodontitis, leukocytosis 
Leukocyte adhesion deficiency type 2 (LAD2) SLC35C1 AR 605881 N + M Rolling, chemotaxis Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay 
Leukocyte adhesion deficiency type 3 (LAD3) FERMT3 AR 607901 N + M +
L + NK 		Adherence, chemotaxis LAD type 1 plus bleeding tendency 
Rac2 deficiency RAC2 AD LOF 608203 N Adherence, chemotaxis
O2− production 		Poor wound healing, leukocytosis 
β-Actin deficiency ACTB AD 102630 N + M Motility Mental retardation, short stature 
Localized juvenile periodontitis FPR1 AR 136537 N Formyl peptide–induced chemotaxis Periodontitis only 
Papillon–Lefèvre syndrome CTSC AR 602365 N + M Chemotaxis Periodontitis, palmoplantar hyperkeratosis in some patients 
WDR1 deficiency WDR1 AR 604734 N Spreading, survival, chemotaxis Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nucleus herniate 
Cystic fibrosis CFTR AR 602421 M only Chemotaxis Respiratory infections, pancreatic insufficiency, elevated sweat chloride 
Neutropenia with combined immune deficiency due to MKL1 deficiency MAP3K9/MKL1 AR 606078 N + M +L + NK Impaired expression of cytoskeletal genes Mild thrombocytopenia 
CCR2 CCR2 AR 219600 M Impaired CCL2-dependent monocyte migration to the lungs and infected tissues Pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including BCG disease 
3. Defects of respiratory burst 
X-linked chronic granulomatous disease (CGD), gp91phox CYBB XL 306400 N + M Killing (faulty O2− production) Infections, autoinflammatory phenotype, IBD
McLeod phenotype in patients with deletions extending into the contiguous Kell locus 
AR CGD CYBA AR 608508 Infections, autoinflammatory phenotype 
CYBC1 618334 
NCF1 608512 
NCF2 608515 
NCF4 613960 
G6PD deficiency class I G6PD XL 305900 N Reduced O2− production Infections 
4. Other nonlymphoid defects 
Pulmonary alveolar proteinosis CSF2RA XL (biallelic mutations in pseudoautosomal gene) 300770 Alveolar macrophages GM-CSF signaling Alveolar proteinosis 
CSF2RB AR 614370 

MDS, myelodysplastic syndrome; IUGR, intrauterine growth retardation; LAD, leukocyte adhesion deficiency; AML, acute myelogenous leukemia; N, neutrophil; M, monocyte; MEL, melanocyte; L, lymphocyte; NK, natural killer; BCG, bacillus Calmette–Guérin; IBD, inflammatory bowel disease.

Total number of defects in Table 5: 45.

New IEIs: 4, DBF4, SRP19, SRPRA, and CCR2 (73, 74, 75).

View large
Table 6.

Defects in intrinsic and innate immunity

DiseaseGenetic defectInheritanceOMIMAffected cellsAffected functionAssociated features
1. Mendelian susceptibility to mycobacterial disease (MSMD) 
IL-12 and IL-23 receptor β1 chain deficiency IL12RB1 AR 601604 L + NK+MAIT IFN-γ secretion Susceptibility to mycobacteria and Salmonella and CMC 
IL-12p40 (IL-12 and IL-23) deficiency IL12B AR 161561 M 
IL-12Rβ2 deficiency IL12RB2 AR 601642 L + NK+MAIT 
IL-23R deficiency IL23R AR 607562 L +NK+MAIT 
IFN-γ receptor deficiency IFNGR1 AR 209950 M + L IFN-γ binding and signaling 
AD 615978 M + L 
IFNGR2 AR 147569 M + L IFN-γ signaling 
STAT1 deficiency STAT1 AD LOF 614892 M + L 
Macrophage gp91phox deficiency
Q231P and T178P 		CYBB XL 300645 Macrophage only Respiratory burst defect in monocytes (not in neutrophils) Isolated susceptibility to mycobacteria 
IRF8 deficiency IRF8 AD 614893 M + L Impaired development of cDCs and Th1* cells Susceptibility to mycobacteria 
AR 226990 M Lack of circulating monocytes and DCs, reduced NK cell numbers and function reported in some patients Susceptibility to mycobacteria and multiple other infectious agents including EBV 
SPPL2a deficiency SPPL2A AR 608238 M + L Impaired development of cDCs and Th1* cells Susceptibility to mycobacteria and Salmonella 
TYK2 deficiency TYK2 AR 611521 M + L Impaired cellular responses to IL-10, IL-12, IL-23, and type I IFNs Susceptibility to intracellular bacteria (mycobacteria, Salmonella) and viruses 
P1104A TYK2 homozygosity AR 176941 L Impaired cellular responses to IL-23 MSMD or tuberculosis 
ISG15 deficiency ISG15 AR 147571  IFN-γ production defect Susceptibility to mycobacteria (BCG), brain calcification 
RORγt deficiency RORC AR 602943 L + NK Lack of functional RORγT protein, IFN-γ production defect, complete absence of IL-17A/F–producing T cells Susceptibility to mycobacteria and candida 
JAK1 deficiency JAK1 AR LOF 147795 N + L Reduced JAK1 activation to cytokines
Reduced IFN-γ production 		Susceptibility to mycobacteria and viruses, urothelial carcinoma 
T-bet deficiency TBX21 AR 619630 L ↓IFN-γ and TNF-α production by γδT cells, MAIT cells, iNKT cells, NK cells, and CD4+ T cells Susceptibility to mycobacteria 
IFN-γ deficiency IFNG AR 618963 L No IFN-γ production by patient T and NK cells Susceptibility to mycobacteria 
IRF1 deficiency IRF1 AR 620668 Lymphocytes, DCs, NK, ILCP, ILCP2 IRF1-dependent responses to IFN-γ are both quantitatively and qualitatively stronger than those to IFN-α/β. IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ, while IFN-α/β–dependent intrinsic immunity to viruses seems unaffected Early-onset severe forms of MSMD due to BCG,M. avium complex. No history of severe viral illnesses. Histoplasmosis in 2 patients 
MCTS1 deficiency MCTS1 XLR 301115 Lymphocytes Impaired cellular responses to IL-23 and partially IL-12, impaired IL-23dep IFN-γ induction by MAIT and γδT cells Life-threatening early-onset BCG disease. Disease was multifocal or disseminated in several cases including osteomyelitis 
2. Epidermodysplasia verruciformis (HPV) 
EVER1 deficiency TMC6 AR 605828 Keratinocytes EVER1, EVER2, and CIB1 form a complex in keratinocytes HPV (group B1) infections and cancer of the skin (typical EV) 
EVER2 deficiency TMC8 605829 
CIB1 deficiency CIB1 618267 
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome CXCR4 AD GOF 162643 Leukocytes Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) Warts (HPV) infection, neutropenia, low B-cell number, hypogammaglobulinemia 
3. Predisposition to severe viral infection 
STAT1 deficiency STAT1 AR LOF 600555 Leukocytes and other cells STAT1-dependent IFN-α/β, INF-γ, and IFN-λ responses Severe viral infections, mycobacterial infection 
STAT2 deficiency STAT2 AR 600556 Leukocytes and other cells STAT2-dependent IFN-α/β, IFN-γ, and IFN-λ responses Severe viral infections (disseminated vaccine-strain measles), influenza, HSV, enterovirus; atypical Kawasaki disease, HLH 
IRF9 deficiency IRF9 AR 618648 Leukocytes and other cells IRF9- and ISGF3-dependent IFN-α/β and IFN-λ responses Severe influenza disease 
IRF7 deficiency IRF7 AR 605047 Leukocytes, plasmacytoid DCs, nonhematopoietic cells IFN-α, IFN-β, and IFN-γ production and IFN-l production 
IFNAR1 deficiency IFNAR1 AR 619935 Leukocytes and other cells IFNAR1-dependent responses to IFN-α/β Severe viral infections (dissemination of yellow fever vaccine and measles vaccine) 
IFNAR2 deficiency IFNAR2 AR 602376 Broadly expressed IFNAR2-dependent responses to IFN-α/β Severe viral infections (disseminated vaccine-strain measles, HHV6) 
CD16 deficiency FCGR3A AR 146740 NK cells Altered NK cell function Severe herpes viral infections, particularly VZV,EBV, and HPV 
MDA5 deficiency IFIH1 AR LOF 606951 Broadly expressed Viral recognition and IFN induction Rhinovirus and other RNA viruses 
NOS2 deficiency NOS2 AR NA Myeloid cells Mutant NOS2 failed to induce nitrous oxide Severe (fatal) susceptibility to CMV-induced disease; pneumocystis pneumonia secondary to CMV; intact responses to infection with other herpesviruses (EBV, VZV, HSV) 
ZNFX1 deficiency ZNFX1 AR 619644 Broadly expressed ↑ ISG in response to poly I/C Severe infections by RNA/DNA viruses, mycobacteria; early-onset severe inflammation affecting liver, brain, kidneys, lungs; virally triggered inflammatory episodes, hepatosplenomegaly, lymphadenopathy 
RNA polymerase III deficiency POLR3A AD 614258 Leukocytes and other cells Impaired viral recognition and IFN induction in response to VZV or poly I:C Severe VZV infection 
POLR3C AD 617454 
POLR3F AD 617455 
MIS-C OAS1 AR  Monocytic phagocytes Excessive inflammatory cytokine production by monocytes Multisystemic inflammatory syndrome in children (MIS-C) after SARS-CoV-2 
OAS2 AR  Monocytic phagocytes Excessive inflammatory cytokine production by monocytes MIS-C 
RNASEL AR  Monocytic phagocytes Excessive inflammatory cytokine production by monocytes MIS-C 
4. Herpes simplex encephalitis (HSE) 
TLR3 deficiency TLR3 AD 613002 CNS-resident cells and fibroblasts TLR3-dependent IFN-α, IFN-β, and IFN-γ response Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here); severe pulmonary influenza; VZV 
AR 
UNC93B1 deficiency UNC93B1 AR 608204 UNC-93B–dependent IFN-α, IFN-β, and IFN-γ response Herpes simplex virus 1 encephalitis 
TRAF3 deficiency TRAF3 AD 601896 TRAF3-dependent IFN-α, IFN-β, and IFN-γ response 
TRIF deficiency TICAM1 AD 607601 TRIF-dependent IFN-α, IFN-β, and IFN-γ response 
AR 
TBK1 deficiency TBK1 AD 604834 TBK1-dependent IFN-α, IFN-β, and IFN-γ response 
IRF3 deficiency IRF3 AD 616532 Low IFN-α/β, production in response to HSV1 and decreased IRF3 phosphorylation 
DBR1 deficiency DBR1 AR 607024 Impaired production of antiviral IFNs HSE of the brainstem. Other viral infections of the brainstem 
SNORA31 deficiency SNORA31 AD 619396 Impaired production of antiviral IFNs Forebrain HSV1 encephalitis 
ATG4A deficiency ATG4 AD NA CNS-resident cells and fibroblasts Impaired HSV2-induced autophagy →increased viral replication and apoptosis of patient fibroblasts Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2 
MAP1LC3B2 deficiency MAP1LC3B2 
RIPK3 deficiency RIPK3 AR NA Neurons Impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection Herpes simplex encephalitis recurrent in one patient. Otherwise, healthy 
GTF3A deficiency GTF3A AR NA Fibroblasts ↓ RNA5SP141 expression results in abrogated RIG-I activation upon HSV-1 infection CVID phenotype, low switched memory B cells, absent IgM. Defect in pneumococcal antibody response. T cells, mostly memory effector phenotype, low TFH and TH17 cells 
IKBKE deficiency IKBKE AD NA Microglia Impaired induction of IFN-β1 (IFNB1) upon HSV-2 infection or dsDNA stimulation. Failure to induce phosphorylation of STING Recurrent HSV-2 meningitis 
5. Predisposition to invasive fungal diseases 
CARD9 deficiency CARD9 AR 607212 Mononuclear phagocytes CARD9 signaling pathway Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections 
6. Predisposition to mucocutaneous candidiasis 
IL-17RA deficiency IL17RA AR 605461 Epithelial cells, fibroblasts, mononuclear phagocytes IL-17RA signaling pathway, and fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E CMC, folliculitis 
IL-17RC deficiency IL17RC AR 610925 IL-17RC signaling pathway, fibroblasts fail to respond to IL-17A and IL-17F CMC 
IL-17F deficiency IL17F AD 606496 T cells IL-17F–containing dimers CMC 
STAT1 GOF STAT1 AD GOF 600555 T cells, B cells, NK, monocytes Increased STAT1 phosphorylation
Low Th17 cells 		CMC, various fungal, bacterial, and viral (HSV) infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy 
ACT1 deficiency TRAF3IP2 AR 607043 T cells, fibroblasts Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E CMC, blepharitis, folliculitis, and macroglossia 
JNK1 haploinsufficiency MAPK8 AD NA T cells, fibroblasts ↓ Th17 cells ex vivo, in vitro, ↓ responses of fibroblasts to IL-17A, IL-17F, ↓ c-Jun/ATF-2-dependent TGF-β signaling CMC, connective tissue disorder (similar to Ehlers–Danlos syndrome) 
7. TLR signaling pathway deficiency 
IRAK4 deficiency IRAK4 AR 606883 Lymphocytes + granulocytes + monocytes TIR-IRAK4 signaling pathway Pyogenic bacterial diseases, severe viral diseases 
MyD88 deficiency MYD88 AR 602170 Lymphocytes + granulocytes + monocytes TIR-MyD88 signaling pathway 
Systemic autoinflammation splenomegaly and anemia (NASA) IRAK4 AR 607676 Lymphocytes Loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production Recurrent episodes of fever, massive splenomegaly, elevated inflammatory markers, and severe hypochromic microcytic anemia 
IRAK1 deficiency IRAK1 XL 300283 Lymphocytes + granulocytes + monocytes TLR-IRAK1 signaling pathway in fibroblasts, TLR7- and TLR8-IRAK1 signaling pathway in EBV-B cells Bacterial infections, X-linked MECP2 deficiency–related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 
TIRAP deficiency TIRAP AR 614382 Lymphocytes + granulocytes + monocytes TIRAP signaling pathway, TLR1/2, TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes Staphylococcal disease during childhood in the patient lacking lipoteichoic acid Abs 
TLR7 deficiency TLR7 XL 301051 Lymphocytes, myeloid cells Impaired responses to TLR7 ligands; reduced production of type 1 IFN Severe COVID-19 infection 
TLR8 GOF TLR8 XL/somatic mutations 301078 Myeloid cells Elevated proinflammatory serum cytokines; increased proinflammatory responses of patient myeloid cells to TLR8 agonists; reduced ability of mutant TLR8 to attenuate TLR7 signaling Early-onset, severe cytopenias, hepatosplenomegaly, lymphadenopathy; progressive autoinflammatory disease 
MD2 deficiency LY96 AR NA Myeloid cells Decreased endocytosis of TLR4 leads to impaired NF-κB signaling and decreased cytokine production Very early-onset inflammatory bowel disease and recurrent infections, pneumonia, and otitis media 
TLR4 deficiency TLR4 AR NA  Impaired TLR4 signaling Inflammatory bowel disease 
8. Other IEIs related to nonhematopoietic tissues 
Isolated congenital asplenia (ICA) RPSA AD 271400 No spleen RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome Bacteremia (encapsulated bacteria) 
HMOX AR 141250 Macrophages HO-1 regulates iron recycling, and heme-dependent damage occurs Hemolysis, nephritis, inflammation 
Trypanosomiasis APOL1 AD 603743 Somatic Pore-forming serum protein Trypanosomiasis 
Acute liver failure due to NBAS deficiency NBAS AR 608025 Somatic and hematopoietic ER stress Fever induces liver failure 
Acute necrotizing encephalopathy RANBP2 AD 601181 Ubiquitous expression Nuclear pore Fever induces acute encephalopathy 
Osteopetrosis CLCN7 AR/AD 602727 Osteoclasts Secretory lysosomes Osteopetrosis with hypocalcemia, neurological features 
SNX10 AR 614780 Osteopetrosis with visual impairment 
OSTM1 AR 607649 Osteopetrosis with hypocalcemia, neurological features 
PLEKHM1 AR 611466 Osteopetrosis 
TCIRG1 AR 604592 Osteopetrosis with hypocalcemia 
TNFRSF11A AR 603499 Osteoclastogenesis Osteopetrosis 
TNFSF11 AR 602642 Stromal Osteoclastogenesis Osteopetrosis with severe growth retardation 
Hidradenitis suppurativa NCSTN AD 605254 Epidermis Notch signaling/gamma-secretase in hair follicle regulates keratinization Verneuil’s disease/hidradenitis suppurativa with acne 
PSEN AD 613737 Verneuil’s disease/hidradenitis suppurativa with cutaneous hyperpigmentation 
PSENEN AD 613736 Verneuil’s disease/hidradenitis suppurativa 
9. Other IEIs related to leukocytes 
IRF4 haploinsufficiency IRF4 AD 601900 Lymphocytes and monocytes IRF4 is a pleiotropic transcription factor Whipple’s disease 
IL-18BP deficiency IL18BP AR 604113 Leukocytes and other cells IL-18BP neutralizes secreted IL-18 Fulminant viral hepatitis 
GATA2 deficiency GATA2 AD 137295 Monocytes + peripheral DC, NK cells Multilineage cytopenia Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMML, lymphedema 
DiseaseGenetic defectInheritanceOMIMAffected cellsAffected functionAssociated features
1. Mendelian susceptibility to mycobacterial disease (MSMD) 
IL-12 and IL-23 receptor β1 chain deficiency IL12RB1 AR 601604 L + NK+MAIT IFN-γ secretion Susceptibility to mycobacteria and Salmonella and CMC 
IL-12p40 (IL-12 and IL-23) deficiency IL12B AR 161561 M 
IL-12Rβ2 deficiency IL12RB2 AR 601642 L + NK+MAIT 
IL-23R deficiency IL23R AR 607562 L +NK+MAIT 
IFN-γ receptor deficiency IFNGR1 AR 209950 M + L IFN-γ binding and signaling 
AD 615978 M + L 
IFNGR2 AR 147569 M + L IFN-γ signaling 
STAT1 deficiency STAT1 AD LOF 614892 M + L 
Macrophage gp91phox deficiency
Q231P and T178P 		CYBB XL 300645 Macrophage only Respiratory burst defect in monocytes (not in neutrophils) Isolated susceptibility to mycobacteria 
IRF8 deficiency IRF8 AD 614893 M + L Impaired development of cDCs and Th1* cells Susceptibility to mycobacteria 
AR 226990 M Lack of circulating monocytes and DCs, reduced NK cell numbers and function reported in some patients Susceptibility to mycobacteria and multiple other infectious agents including EBV 
SPPL2a deficiency SPPL2A AR 608238 M + L Impaired development of cDCs and Th1* cells Susceptibility to mycobacteria and Salmonella 
TYK2 deficiency TYK2 AR 611521 M + L Impaired cellular responses to IL-10, IL-12, IL-23, and type I IFNs Susceptibility to intracellular bacteria (mycobacteria, Salmonella) and viruses 
P1104A TYK2 homozygosity AR 176941 L Impaired cellular responses to IL-23 MSMD or tuberculosis 
ISG15 deficiency ISG15 AR 147571  IFN-γ production defect Susceptibility to mycobacteria (BCG), brain calcification 
RORγt deficiency RORC AR 602943 L + NK Lack of functional RORγT protein, IFN-γ production defect, complete absence of IL-17A/F–producing T cells Susceptibility to mycobacteria and candida 
JAK1 deficiency JAK1 AR LOF 147795 N + L Reduced JAK1 activation to cytokines
Reduced IFN-γ production 		Susceptibility to mycobacteria and viruses, urothelial carcinoma 
T-bet deficiency TBX21 AR 619630 L ↓IFN-γ and TNF-α production by γδT cells, MAIT cells, iNKT cells, NK cells, and CD4+ T cells Susceptibility to mycobacteria 
IFN-γ deficiency IFNG AR 618963 L No IFN-γ production by patient T and NK cells Susceptibility to mycobacteria 
IRF1 deficiency IRF1 AR 620668 Lymphocytes, DCs, NK, ILCP, ILCP2 IRF1-dependent responses to IFN-γ are both quantitatively and qualitatively stronger than those to IFN-α/β. IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ, while IFN-α/β–dependent intrinsic immunity to viruses seems unaffected Early-onset severe forms of MSMD due to BCG,M. avium complex. No history of severe viral illnesses. Histoplasmosis in 2 patients 
MCTS1 deficiency MCTS1 XLR 301115 Lymphocytes Impaired cellular responses to IL-23 and partially IL-12, impaired IL-23dep IFN-γ induction by MAIT and γδT cells Life-threatening early-onset BCG disease. Disease was multifocal or disseminated in several cases including osteomyelitis 
2. Epidermodysplasia verruciformis (HPV) 
EVER1 deficiency TMC6 AR 605828 Keratinocytes EVER1, EVER2, and CIB1 form a complex in keratinocytes HPV (group B1) infections and cancer of the skin (typical EV) 
EVER2 deficiency TMC8 605829 
CIB1 deficiency CIB1 618267 
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome CXCR4 AD GOF 162643 Leukocytes Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) Warts (HPV) infection, neutropenia, low B-cell number, hypogammaglobulinemia 
3. Predisposition to severe viral infection 
STAT1 deficiency STAT1 AR LOF 600555 Leukocytes and other cells STAT1-dependent IFN-α/β, INF-γ, and IFN-λ responses Severe viral infections, mycobacterial infection 
STAT2 deficiency STAT2 AR 600556 Leukocytes and other cells STAT2-dependent IFN-α/β, IFN-γ, and IFN-λ responses Severe viral infections (disseminated vaccine-strain measles), influenza, HSV, enterovirus; atypical Kawasaki disease, HLH 
IRF9 deficiency IRF9 AR 618648 Leukocytes and other cells IRF9- and ISGF3-dependent IFN-α/β and IFN-λ responses Severe influenza disease 
IRF7 deficiency IRF7 AR 605047 Leukocytes, plasmacytoid DCs, nonhematopoietic cells IFN-α, IFN-β, and IFN-γ production and IFN-l production 
IFNAR1 deficiency IFNAR1 AR 619935 Leukocytes and other cells IFNAR1-dependent responses to IFN-α/β Severe viral infections (dissemination of yellow fever vaccine and measles vaccine) 
IFNAR2 deficiency IFNAR2 AR 602376 Broadly expressed IFNAR2-dependent responses to IFN-α/β Severe viral infections (disseminated vaccine-strain measles, HHV6) 
CD16 deficiency FCGR3A AR 146740 NK cells Altered NK cell function Severe herpes viral infections, particularly VZV,EBV, and HPV 
MDA5 deficiency IFIH1 AR LOF 606951 Broadly expressed Viral recognition and IFN induction Rhinovirus and other RNA viruses 
NOS2 deficiency NOS2 AR NA Myeloid cells Mutant NOS2 failed to induce nitrous oxide Severe (fatal) susceptibility to CMV-induced disease; pneumocystis pneumonia secondary to CMV; intact responses to infection with other herpesviruses (EBV, VZV, HSV) 
ZNFX1 deficiency ZNFX1 AR 619644 Broadly expressed ↑ ISG in response to poly I/C Severe infections by RNA/DNA viruses, mycobacteria; early-onset severe inflammation affecting liver, brain, kidneys, lungs; virally triggered inflammatory episodes, hepatosplenomegaly, lymphadenopathy 
RNA polymerase III deficiency POLR3A AD 614258 Leukocytes and other cells Impaired viral recognition and IFN induction in response to VZV or poly I:C Severe VZV infection 
POLR3C AD 617454 
POLR3F AD 617455 
MIS-C OAS1 AR  Monocytic phagocytes Excessive inflammatory cytokine production by monocytes Multisystemic inflammatory syndrome in children (MIS-C) after SARS-CoV-2 
OAS2 AR  Monocytic phagocytes Excessive inflammatory cytokine production by monocytes MIS-C 
RNASEL AR  Monocytic phagocytes Excessive inflammatory cytokine production by monocytes MIS-C 
4. Herpes simplex encephalitis (HSE) 
TLR3 deficiency TLR3 AD 613002 CNS-resident cells and fibroblasts TLR3-dependent IFN-α, IFN-β, and IFN-γ response Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here); severe pulmonary influenza; VZV 
AR 
UNC93B1 deficiency UNC93B1 AR 608204 UNC-93B–dependent IFN-α, IFN-β, and IFN-γ response Herpes simplex virus 1 encephalitis 
TRAF3 deficiency TRAF3 AD 601896 TRAF3-dependent IFN-α, IFN-β, and IFN-γ response 
TRIF deficiency TICAM1 AD 607601 TRIF-dependent IFN-α, IFN-β, and IFN-γ response 
AR 
TBK1 deficiency TBK1 AD 604834 TBK1-dependent IFN-α, IFN-β, and IFN-γ response 
IRF3 deficiency IRF3 AD 616532 Low IFN-α/β, production in response to HSV1 and decreased IRF3 phosphorylation 
DBR1 deficiency DBR1 AR 607024 Impaired production of antiviral IFNs HSE of the brainstem. Other viral infections of the brainstem 
SNORA31 deficiency SNORA31 AD 619396 Impaired production of antiviral IFNs Forebrain HSV1 encephalitis 
ATG4A deficiency ATG4 AD NA CNS-resident cells and fibroblasts Impaired HSV2-induced autophagy →increased viral replication and apoptosis of patient fibroblasts Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2 
MAP1LC3B2 deficiency MAP1LC3B2 
RIPK3 deficiency RIPK3 AR NA Neurons Impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection Herpes simplex encephalitis recurrent in one patient. Otherwise, healthy 
GTF3A deficiency GTF3A AR NA Fibroblasts ↓ RNA5SP141 expression results in abrogated RIG-I activation upon HSV-1 infection CVID phenotype, low switched memory B cells, absent IgM. Defect in pneumococcal antibody response. T cells, mostly memory effector phenotype, low TFH and TH17 cells 
IKBKE deficiency IKBKE AD NA Microglia Impaired induction of IFN-β1 (IFNB1) upon HSV-2 infection or dsDNA stimulation. Failure to induce phosphorylation of STING Recurrent HSV-2 meningitis 
5. Predisposition to invasive fungal diseases 
CARD9 deficiency CARD9 AR 607212 Mononuclear phagocytes CARD9 signaling pathway Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections 
6. Predisposition to mucocutaneous candidiasis 
IL-17RA deficiency IL17RA AR 605461 Epithelial cells, fibroblasts, mononuclear phagocytes IL-17RA signaling pathway, and fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E CMC, folliculitis 
IL-17RC deficiency IL17RC AR 610925 IL-17RC signaling pathway, fibroblasts fail to respond to IL-17A and IL-17F CMC 
IL-17F deficiency IL17F AD 606496 T cells IL-17F–containing dimers CMC 
STAT1 GOF STAT1 AD GOF 600555 T cells, B cells, NK, monocytes Increased STAT1 phosphorylation
Low Th17 cells 		CMC, various fungal, bacterial, and viral (HSV) infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy 
ACT1 deficiency TRAF3IP2 AR 607043 T cells, fibroblasts Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E CMC, blepharitis, folliculitis, and macroglossia 
JNK1 haploinsufficiency MAPK8 AD NA T cells, fibroblasts ↓ Th17 cells ex vivo, in vitro, ↓ responses of fibroblasts to IL-17A, IL-17F, ↓ c-Jun/ATF-2-dependent TGF-β signaling CMC, connective tissue disorder (similar to Ehlers–Danlos syndrome) 
7. TLR signaling pathway deficiency 
IRAK4 deficiency IRAK4 AR 606883 Lymphocytes + granulocytes + monocytes TIR-IRAK4 signaling pathway Pyogenic bacterial diseases, severe viral diseases 
MyD88 deficiency MYD88 AR 602170 Lymphocytes + granulocytes + monocytes TIR-MyD88 signaling pathway 
Systemic autoinflammation splenomegaly and anemia (NASA) IRAK4 AR 607676 Lymphocytes Loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production Recurrent episodes of fever, massive splenomegaly, elevated inflammatory markers, and severe hypochromic microcytic anemia 
IRAK1 deficiency IRAK1 XL 300283 Lymphocytes + granulocytes + monocytes TLR-IRAK1 signaling pathway in fibroblasts, TLR7- and TLR8-IRAK1 signaling pathway in EBV-B cells Bacterial infections, X-linked MECP2 deficiency–related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 
TIRAP deficiency TIRAP AR 614382 Lymphocytes + granulocytes + monocytes TIRAP signaling pathway, TLR1/2, TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes Staphylococcal disease during childhood in the patient lacking lipoteichoic acid Abs 
TLR7 deficiency TLR7 XL 301051 Lymphocytes, myeloid cells Impaired responses to TLR7 ligands; reduced production of type 1 IFN Severe COVID-19 infection 
TLR8 GOF TLR8 XL/somatic mutations 301078 Myeloid cells Elevated proinflammatory serum cytokines; increased proinflammatory responses of patient myeloid cells to TLR8 agonists; reduced ability of mutant TLR8 to attenuate TLR7 signaling Early-onset, severe cytopenias, hepatosplenomegaly, lymphadenopathy; progressive autoinflammatory disease 
MD2 deficiency LY96 AR NA Myeloid cells Decreased endocytosis of TLR4 leads to impaired NF-κB signaling and decreased cytokine production Very early-onset inflammatory bowel disease and recurrent infections, pneumonia, and otitis media 
TLR4 deficiency TLR4 AR NA  Impaired TLR4 signaling Inflammatory bowel disease 
8. Other IEIs related to nonhematopoietic tissues 
Isolated congenital asplenia (ICA) RPSA AD 271400 No spleen RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome Bacteremia (encapsulated bacteria) 
HMOX AR 141250 Macrophages HO-1 regulates iron recycling, and heme-dependent damage occurs Hemolysis, nephritis, inflammation 
Trypanosomiasis APOL1 AD 603743 Somatic Pore-forming serum protein Trypanosomiasis 
Acute liver failure due to NBAS deficiency NBAS AR 608025 Somatic and hematopoietic ER stress Fever induces liver failure 
Acute necrotizing encephalopathy RANBP2 AD 601181 Ubiquitous expression Nuclear pore Fever induces acute encephalopathy 
Osteopetrosis CLCN7 AR/AD 602727 Osteoclasts Secretory lysosomes Osteopetrosis with hypocalcemia, neurological features 
SNX10 AR 614780 Osteopetrosis with visual impairment 
OSTM1 AR 607649 Osteopetrosis with hypocalcemia, neurological features 
PLEKHM1 AR 611466 Osteopetrosis 
TCIRG1 AR 604592 Osteopetrosis with hypocalcemia 
TNFRSF11A AR 603499 Osteoclastogenesis Osteopetrosis 
TNFSF11 AR 602642 Stromal Osteoclastogenesis Osteopetrosis with severe growth retardation 
Hidradenitis suppurativa NCSTN AD 605254 Epidermis Notch signaling/gamma-secretase in hair follicle regulates keratinization Verneuil’s disease/hidradenitis suppurativa with acne 
PSEN AD 613737 Verneuil’s disease/hidradenitis suppurativa with cutaneous hyperpigmentation 
PSENEN AD 613736 Verneuil’s disease/hidradenitis suppurativa 
9. Other IEIs related to leukocytes 
IRF4 haploinsufficiency IRF4 AD 601900 Lymphocytes and monocytes IRF4 is a pleiotropic transcription factor Whipple’s disease 
IL-18BP deficiency IL18BP AR 604113 Leukocytes and other cells IL-18BP neutralizes secreted IL-18 Fulminant viral hepatitis 
GATA2 deficiency GATA2 AD 137295 Monocytes + peripheral DC, NK cells Multilineage cytopenia Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMML, lymphedema 

NF-κB, nuclear factor kappa B; TIR, Toll and interleukin-1 receptor; IFN, interferon; TLR, Toll-like receptor; MDC, myeloid dendritic cell; CNS, central nervous system; CMC, chronic mucocutaneous candidiasis; HPV, human papillomavirus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; CVID, common variable immunodeficiency; Abs, antibodies.

Total number of mutant genes in Table 6: 86 diseases with 2 entries for IRAK4 counted separately as they constitute different genetic mechanisms and associated phenotypes. GATA2 was moved from nonlymphoid disease table to Table 6, subtable 9.

New IEIs: 10, IRF1, MCTS1, OAS1, OAS2, RNASEL, RIPK3, MD2, TLR4, GTF3A, and IKBKE (76, 77, 78, 79, 80, 81, 82, 83).

* after Th1 refers to Th1 cells, which are a specificsubset of human CD4+ T cells and are specifically affected by the indicatedgene mutations i.e. IRF8, SPPL2A.

View large
Table 7.

Autoinflammatory disorders

DiseaseGenetic defectInheritanceOMIMT cellsB cellsFunctional defectAssociated features
1. Type 1 interferonopathies 
AD STING-associated vasculopathy, infantile-onset (SAVI) TMEM173** (STING) AD 612374 Not assessed Not assessed STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL 
AR STING-associated vasculopathy, infantile-onset (SAVI) AR GOF 615934 Not assessed Not assessed STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN FTT, early-onset rash, fever, dyspnea, interstitial lung disease/pneumonitis, polyarthritis, autoAbs, increased inflammatory markers, IFN gene signature. Phenocopy of SAVI due to AD GOF TMEM173 
ADA2 deficiency ADA2 AR 607575 Not assessed Not assessed ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; some patients develop hypogammaglobulinemia 
TREX1 deficiency, Aicardi–Goutières syndrome 1 (AGS1) TREX1 AR 606609 Not assessed Not assessed Intracellular accumulation of abnormal ssDNA species leading to increased type I IFN production Classical AGS, SLE, FCL 
AD 
RNASEH2B deficiency, AGS2 RNASEH2B AR 610326 Not assessed Not assessed Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production Classical AGS, SP 
RNASEH2C deficiency, AGS3 RNASEH2C AR 610330 Not assessed Not assessed Classical AGS 
RNASEH2A deficiency, AGS4 RNASEH2A AR 606034 Not assessed Not assessed Classical AGS 
SAMHD1 deficiency, AGS5 SAMHD1 AR 606754 Not assessed Not assessed Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production Classical AGS, FCL 
ADAR1 deficiency, AGS6 ADAR1 AR 615010 Not assessed Not assessed Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production Classical AGS, BSN, SP 
AD (G1007R) NA 
Aicardi–Goutières syndrome 7 (AGS7) IFIH1 AD GOF 615846 Not assessed Not assessed IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule Classical AGS, SLE, SP, SMS 
DNase II deficiency DNASE2 AR 619858 Not assessed Not assessed DNase II degrades and eliminates DNA. Loss of DNase II activity induces type I interferon signaling AGS 
LSM11 deficiency LSM11 AR 619486 Not assessed Not assessed Increased IFN signaling in fibroblasts AGS, type 1 IFN-opathy 
RNU7-1 deficiency RNU7-1 AR 619487 Not assessed Not assessed Increased IFN signaling in fibroblasts AGS, type 1 IFN-opathy 
ARF1 deficiency ARF1 AD 103180 Not assessed Not assessed Increased type I IFN signaling in cell lines and patient cells AGS, type 1 IFN-opathy 
Pediatric SLE due to DNASE1L3 deficiency DNASE1L3 AR 614420   DNASE1L3 is an endonuclease that degrades extracellular DNA. DNASE1L3 deficiency decreases clearance of apoptotic cells Very early-onset SLE, reduced complement levels, autoantibodies (dsDNA, ANCA), lupus nephritis, hypocomplementemic urticarial vasculitis syndrome 
Spondyloenchondrodysplasia with immune dysregulation (SPENCD) ACP5 AR 171640 Not assessed Not assessed Upregulation of IFN through mechanism possibly relating to pDCS Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections 
USP18 deficiency USP18 AR 607057 Not assessed Not assessed Defective negative regulation of ISG15 leading to increased IFN TORCH-like syndrome, autoinflammation, and mycobacterial disease 
OAS1 GOF OAS1 AD GOF 618042  Low Increased interferon from recognition of RNA Pulmonary alveolar proteinosis, skin rash 
CDC42 deficiency CDC42 AD 616737 Normal/decreased Normal/decreased ↑serum levels of IL-1, IL-18, IFN-α↑, ferritin, sCD25, CRP, etc. Mutation affects actin function, ↓ NK cell cytotoxicity Neonatal onset: pancytopenia, fever, rash, hepatosplenomegaly, multisystemic inflammation, myelofibrosis/proliferation, HLH, enterocolitis; recurrent GIT/URT infections; neurodevelopmental delay, FTT 
STAT2 loss of negative regulation STAT2 AR 616636 Increased Normal Patient cells hypersensitive to IFN-α, GOF for induction of the late (not early) response to type 1 IFNs due to impaired interaction of mutant STAT2 with USP18, a negative regulator of type 1 IFN responses Severe fatal early-onset autoinflammation, ↑serum IFN-α, IL-6, TNF-α, phenocopy of USP18 deficiency 
ATAD3A deficiency ATAD3A AD/AR 617183 Not assessed Not assessed Elevated ISG expression, increased serum type 1 IFNs Predominantly neurological defects (development delay, spasticity) 
RELA haploinsufficiency RELA AD 618287 Normal/increased Normal  Chronic mucocutaneous ulceration
Impaired NF-κB activation; reduced production of inflammatory cytokines 
RELA interferonopathya RELA AD DN 618287   Leukocyte TLR7-dependent type I/III IFN production Patients with RELA DN mutations shared clinical phenotypes with RELA haploinsufficiency, presenting chronic mucocutaneous ulcerations and autoimmune hematological disorders such as immune thrombocytopenia (ITP) and neutropenia. However, patients with RELA DN mutations additionally presented periodic fever, IBD juvenile idiopathic arthritis (JIA), and skin involvement 
DiseaseGenetic defectInheritanceOMIMT cellsB cellsFunctional defectAssociated features
1. Type 1 interferonopathies 
AD STING-associated vasculopathy, infantile-onset (SAVI) TMEM173** (STING) AD 612374 Not assessed Not assessed STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL 
AR STING-associated vasculopathy, infantile-onset (SAVI) AR GOF 615934 Not assessed Not assessed STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN FTT, early-onset rash, fever, dyspnea, interstitial lung disease/pneumonitis, polyarthritis, autoAbs, increased inflammatory markers, IFN gene signature. Phenocopy of SAVI due to AD GOF TMEM173 
ADA2 deficiency ADA2 AR 607575 Not assessed Not assessed ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; some patients develop hypogammaglobulinemia 
TREX1 deficiency, Aicardi–Goutières syndrome 1 (AGS1) TREX1 AR 606609 Not assessed Not assessed Intracellular accumulation of abnormal ssDNA species leading to increased type I IFN production Classical AGS, SLE, FCL 
AD 
RNASEH2B deficiency, AGS2 RNASEH2B AR 610326 Not assessed Not assessed Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production Classical AGS, SP 
RNASEH2C deficiency, AGS3 RNASEH2C AR 610330 Not assessed Not assessed Classical AGS 
RNASEH2A deficiency, AGS4 RNASEH2A AR 606034 Not assessed Not assessed Classical AGS 
SAMHD1 deficiency, AGS5 SAMHD1 AR 606754 Not assessed Not assessed Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production Classical AGS, FCL 
ADAR1 deficiency, AGS6 ADAR1 AR 615010 Not assessed Not assessed Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production Classical AGS, BSN, SP 
AD (G1007R) NA 
Aicardi–Goutières syndrome 7 (AGS7) IFIH1 AD GOF 615846 Not assessed Not assessed IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule Classical AGS, SLE, SP, SMS 
DNase II deficiency DNASE2 AR 619858 Not assessed Not assessed DNase II degrades and eliminates DNA. Loss of DNase II activity induces type I interferon signaling AGS 
LSM11 deficiency LSM11 AR 619486 Not assessed Not assessed Increased IFN signaling in fibroblasts AGS, type 1 IFN-opathy 
RNU7-1 deficiency RNU7-1 AR 619487 Not assessed Not assessed Increased IFN signaling in fibroblasts AGS, type 1 IFN-opathy 
ARF1 deficiency ARF1 AD 103180 Not assessed Not assessed Increased type I IFN signaling in cell lines and patient cells AGS, type 1 IFN-opathy 
Pediatric SLE due to DNASE1L3 deficiency DNASE1L3 AR 614420   DNASE1L3 is an endonuclease that degrades extracellular DNA. DNASE1L3 deficiency decreases clearance of apoptotic cells Very early-onset SLE, reduced complement levels, autoantibodies (dsDNA, ANCA), lupus nephritis, hypocomplementemic urticarial vasculitis syndrome 
Spondyloenchondrodysplasia with immune dysregulation (SPENCD) ACP5 AR 171640 Not assessed Not assessed Upregulation of IFN through mechanism possibly relating to pDCS Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections 
USP18 deficiency USP18 AR 607057 Not assessed Not assessed Defective negative regulation of ISG15 leading to increased IFN TORCH-like syndrome, autoinflammation, and mycobacterial disease 
OAS1 GOF OAS1 AD GOF 618042  Low Increased interferon from recognition of RNA Pulmonary alveolar proteinosis, skin rash 
CDC42 deficiency CDC42 AD 616737 Normal/decreased Normal/decreased ↑serum levels of IL-1, IL-18, IFN-α↑, ferritin, sCD25, CRP, etc. Mutation affects actin function, ↓ NK cell cytotoxicity Neonatal onset: pancytopenia, fever, rash, hepatosplenomegaly, multisystemic inflammation, myelofibrosis/proliferation, HLH, enterocolitis; recurrent GIT/URT infections; neurodevelopmental delay, FTT 
STAT2 loss of negative regulation STAT2 AR 616636 Increased Normal Patient cells hypersensitive to IFN-α, GOF for induction of the late (not early) response to type 1 IFNs due to impaired interaction of mutant STAT2 with USP18, a negative regulator of type 1 IFN responses Severe fatal early-onset autoinflammation, ↑serum IFN-α, IL-6, TNF-α, phenocopy of USP18 deficiency 
ATAD3A deficiency ATAD3A AD/AR 617183 Not assessed Not assessed Elevated ISG expression, increased serum type 1 IFNs Predominantly neurological defects (development delay, spasticity) 
RELA haploinsufficiency RELA AD 618287 Normal/increased Normal  Chronic mucocutaneous ulceration
Impaired NF-κB activation; reduced production of inflammatory cytokines 
RELA interferonopathya RELA AD DN 618287   Leukocyte TLR7-dependent type I/III IFN production Patients with RELA DN mutations shared clinical phenotypes with RELA haploinsufficiency, presenting chronic mucocutaneous ulcerations and autoimmune hematological disorders such as immune thrombocytopenia (ITP) and neutropenia. However, patients with RELA DN mutations additionally presented periodic fever, IBD juvenile idiopathic arthritis (JIA), and skin involvement 
DiseaseGenetic defectInheritanceOMIMAffected cellsFunctional defectAssociated features
2. Defects affecting the inflammasome 
Familial Mediterranean fever (FMF) MEFV** AR LOF 249100 Mature granulocytes, cytokine-activated monocytes Increased pyrin inflammasome-mediated induction of IL-1β Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease, SAA amyloidosis 
AD 134610 Mature granulocytes, cytokine-activated monocytes Usually, M694del variant. Other missense variants in the B-Box and CC domains cause constitutive pyrin activation 
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia, and hypercalprotectinemia PSTPIP1 AD 604416 PMNs, monocytes Activation of the pyrin inflammasome; high production of IL-1 and IL-18 cytokines; interferon signature Destructive arthritis, inflammatory skin rash, myositis 
Mevalonate kinase deficiency (hyper-IgD syndrome/HIDS) MVK AR 260920 Somatic and hematopoietic Defect in production of isoprenoids, which are synthesized via mevalonate pathway and play a role in regulation of many signaling pathways Periodic fever and leukocytosis with usually high IgD levels 
PMVK deficiency PMVK AR NA Leukocytes Similar to MVK deficiency, increased IL-1β Recurrent fever episodes, arthritis, and cytopenia 
Muckle–Wells syndrome NLRP3** AD GOF 191900 PMNs Monocytes Activation of cryopyrin inflammasome results in increased production of IL-1/IL-18 cytokines and cell death via pyroptosis Urticaria, SNHL, SAA amyloidosis 
Familial cold autoinflammatory syndrome 1 AD GOF 120100 PMNs, monocytes Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure 
Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA) AD GOF 607115 PMNs, chondrocytes Neonatal-onset rash, chronic meningitis, and arthropathy with fever and inflammation 
Keratitis fugax hereditaria associated with c.61G>C
NLRP3 		AD GOF 606416  Episodic conjunctival injection, ocular pain, photophobia, foreign body sensation, and excessive tearing during acute attacks. Corneal opacities during attacks 
Familial cold autoinflammatory syndrome 2 NLRP12 AD GOF 611762 PMNs, monocytes Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure 
NLRC4-MAS (macrophage-activating syndrome) NLRC4 AD GOF 616050 PMNs, monocytes, macrophages, intestinal epithelial cells GOF mutation in NLRC4 results in elevated secretion of IL-1β and IL-18, as well as macrophage activation Severe enterocolitis and macrophage activation syndrome 
Familial cold autoinflammatory syndrome 4 616115 
APLAID or autoinflammation, antibody deficiency, and immune dysregulation Missense variants
PLCG2
Small intragenic deletions 		AD GOF/LOF 614878 B cells, NK, mast cells Mutations affect the autoinhibitory domains and activate NF-κB and MAPK pathways Cold urticaria hypogammaglobulinemia, impaired humoral immunity, autoantibodies, autoinflammation, granulomas 
PLAID or familial cold autoinflammatory syndrome 3 614468 
Autoinflammation with arthritis and dyskeratosis (AIADK; NLRP1 deficiency) NLRP1 AR 617388 Keratinocytes and leukocytes Systemic elevation of IL-18, IL-1β, caspase 1, suggesting activation of NLRP1 inflammasome Dyskeratosis, autoimmunity, and arthritis 
NLRP1 GOF NLRP1 AD GOF 615225 Keratinocytes Spontaneous production of IL-1β and IL-18 cytokines in keratinocytes Palmoplantar carcinoma, corneal scarring; recurrent respiratory papillomatosis 
Autoinflammation with episodic fever and lymphadenopathy/cleavage-resistant RIPK1-induced autoinflammatory syndrome/CRIA RIPK1 AD 618852 Leukocytes and fibroblasts TNF-induced cell death via apoptosis and necroptosis Long-lasting fever episodes, lymphadenopathy, splenohepatomegaly, ulcers, arthralgia, GI features 
Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) LPIN2 AR 609628 Neutrophils, bone marrow cells Dysregulation in cholesterol synthesis impairs the negative regulation of NLRP3 in macrophages resulting in high production of IL-1 Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders 
3. Non-inflammasome–related conditions 
TNF receptor–associated periodic syndrome (TRAPS) TNFRSF1A** AD 142680 PMNs, monocytes Mutations in the extracellular domain of 55-kD TNF receptor cause protein misfolding and intracellular receptor retention resulting in upregulation of ER stress Recurrent fever, serositis, rash, and ocular or joint inflammation 
Blau syndrome NOD2** AD 186580 Monocytes, intestinal epithelial cells Mutations in nucleotide binding site of CARD15 result in constitutive activation of NOD2 noadosome nd upregulation of NF-κB signaling Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies; 30% develop Crohn’s colitis 
ADAM17 deficiency ADAM17 AR 614328 Leukocytes and epithelial cells Defective TNF-α production Early-onset diarrhea and skin lesions 
DIRA (deficiency of the interleukin-1 receptor antagonist) IL1RN AR 612852 PMNs, monocytes Mutations in the IL-1 receptor antagonist allow unopposed action of IL-1α and IL-1β Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis 
Loss of IL-1R1 sensitivity to IL-Ra (LIRSA/CRMO3) (1 patient) IL-1R1 AD 259680 T cells and B cells Activated myeloid cells. Loss of IL-1R1 biding to endogenous IL-Ra Arthritis, osteolytic/sclerotic bone lesions, poor growth, no rash, no fever 
DITRA (deficiency of IL-36 receptor antagonist) IL36RN AR 614204 Keratinocytes, leukocytes Mutations in the IL-36 receptor antagonist allow unopposed action of IL-1α and IL-1β Pustular psoriasis 
Histiocytosis-lymphadenopathy plus syndrome/H syndrome (ENT3) SLC29A3 AR 602782 Leukocytes, histiocytes Defect in nucleoside transport functions of hENT3 leads to histiocytic infiltration of numerous organs Hyperpigmentation hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally hyperglycemia/diabetes mellitus 
CAMPS (CARD14-mediated psoriasis) CARD14 AD 602723 Mainly in keratinocytes Mutations in CARD14 activate the NF-κB pathway and production of IL-8 Psoriasis 
Cherubism SH3BP2 AD 118400 Stromal cells, bone cells Hyperactivated macrophages and osteoclasts, increased NF-κB signaling Bone degeneration in jaws 
PRAAS-CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) PSMB8* AR and AD 256040 Keratinocytes, B-cell adipose cells Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature Contractures, panniculitis, ICC, fevers 
PSMG2 AR 609702 Lymphocytes Panniculitis, lipodystrophy, autoimmune hemolytic anemia 
PSMB10 AR 619175 Lymphocytes Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature Periorbital and hand–foot annular rash (neutrophilic dermatosis), microcytic anemia, long slender fingers, hepatomegaly and splenomegaly 
PSMB9 AR or digenic or DN 617591 Lymphocytes Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature  
PSMB4 AR or digenic 617591 Lymphocytes Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature Panniculitis, lipodystrophy, autoimmune hemolytic anemia 
PRAID POMP AD 618048 Lymphocytes Increased accumulation of ubiquitinated proteins and ER stress with increased IFN signaling mediated by increased PKR signaling CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)/ interstitial lung disease in one patient, liver disease in one patient. Recurrent and opportunistic infections. Low CD8 T cells, skewing toward naïve T cells. Low B cells and positive autoantibodies 
PSMB9 deficiency (G156D) PSMB9 AD (DN LOF) 617591 Leukocytes (mild pancytopenia) Decreased protein expression and reduced proteasome activities. Elevated levels of inflammatory cytokines (IL-6, IL-18, IP-10, IFN-α), liver enzymes in blood and CSF (IFN-α), hyperactivation of IFN-α, pSTAT1 Severe autoinflammatory phenotype (neonatal-onset fever, skin rash, myositis, severe pulmonary hypertension, basal ganglia calcification), periodic inflammatory exacerbation; immunodeficiency. Partial phenocopy of PRAAS 
Autoinflammation with neurodevelopmental disease PSMD12 AR 617516 CNS, lymphocytes ↑ peripheral blood type I IFN gene signature has been reported for some patients Intellectual disability, developmental delay, urticarial skin rash, elevated interferon signature 
COPA syndrome COPA AD 601924 PMN and tissue-specific cells Defective intracellular transport via the coat protein complex I (COPI). Exacerbated STING-mediated type I interferon response Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production 
Otulipenia/ORAS OTULIN AR/AD 615712 Leukocytes, fibroblasts Increase LUBAC induction of NF-κB and interferon activation leading to high proinflammatory cytokine levels. Increase in TNF-induced cell death Fever, diarrhea, skin abscesses, panniculitis 
Dominant negative OTULIN-related autoinflammatory syndrome (3 patients) OTULIN AD 615712 Lymphocytes and fibroblasts Decreased catalytic activity, accumulation of linear ubiquitin chains, increased TNF-induced cell death, Spontaneous systemic inflammation 
OTULIN haploinsufficiency OTULIN AD 615712 Epithelial cells Increased activity of caveolin-1 stabilizes ADAM10 receptor for S. aureus toxin Susceptibility to S. aureus infections in epithelial cells 
Haploinsufficiency of A20/HA20 TNFAIP3 AD 616744 Lymphocytes Defective inhibition of NF-κB signaling pathway Arthralgia, mucosal ulcers, ocular inflammation 
AP1S3 deficiency AP1S3 AR 615781 Keratinocytes Disrupted TLR3 translocation Pustular psoriasis 
ALPI deficiency ALPI AR 171740 Intestinal epithelial cells Deficient inhibition of LPS in intestine Inflammatory bowel disease 
TRIM22 TRIM22 AR 606559 Macrophages, intestinal epithelial cells Granulomatous colitis Inflammatory bowel disease 
T-cell lymphoma subcutaneous panniculitis-like (TIM3 deficiency) HAVCR2 AR 618398 Leukocytes Increased inflammasome activity due to defective checkpoint signaling Panniculitis, HLH, polyclonal cutaneous T-cell infiltrates or T-cell lymphoma 
C2orf69 deficiency (28 patients) C2orf69 AR 619423 Outer mitochondrial membrane of all cells C2orf69 regulates mitochondrial function; protein deficiency causes respiratory chain defects Early-onset severe autoinflammation disorder, often fatal. Global developmental delay, with recurrent seizures, muscle weakness due to glycogen deposits 
SYK GOF SYK AD GOF 619381 Lymphocytes, osteoclasts Increased SYK phosphorylation, enhanced NF-κB, JNK, and ERK signaling. Mutated T cells are hypersensitive to stimulation and produce various proinflammatory chemokines and cytokines (IL-17, IL-22, TNF, IFN-γ) Recurrent infections, multi-organ inflammation/inflammatory disease (gut, skin, CNS, lung, liver), B-cell lymphoma reported in 2 pts 
HCK GOF HCK AD GOF 620296 Lymphocytes Increased kinase activity of HCK mutant in vitro; ↑ production of inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), ROS Cutaneous vasculitis, inflammatory leukocyte infiltration of the lungs (pulmonary fibrosis) and skin, anemia, hepatosplenomegaly 
NEMO exon 5 deletion IKBKG XL 301081 Leukocytes Mutant NEMO lacks exon 5 (NEMO-Dex5), fails to bind TBK1; NEMO-Dex5 stabilized IKKi, strong NF-κB, and interferon gene expression signatures Fever, skin rash, systemic autoinflammation, infections, CNS involvement, panniculitis, uveitis, hepatosplenomegaly, ectodermal dysplasia 
TBK1 deficiency TBK1 AR 620880 Leukocytes Autoinflammation driven by TNF-induced RIPK1-dependent cell death Chronic systemic autoinflammation (polyarthritis, vasculitis, rash); delayed neurocognitive development 
Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) ALPK1 AD 614979 Lymphocytes Immune activation with increased NF-κB signaling, STAT1 phosphorylation, and interferon gene expression signature Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache, fever, arthritis, colitis, dental abnormalities 
LYN GOF
Systemic autoinflammatory disease with vasculitis, SAIDV 		LYN AD GOF 620376 Endothelial cells and neutrophils Activated endothelial cells, constitutively active neutrophils Diffuse purpuric rash/atopic dermatitis, fever, hepatosplenomegaly, liver fibrosis/calcifications, arthritis, periorbital edema, respiratory insufficiency, colitis, poor growth 
SHARPIN deficiency SHARPIN AR 620795 Impaired development of germinal centers in secondary lymphoid organs, low CD20+cells, increased memory B cells Defect in LUBAC function, attenuated canonical NF-κB responses, increased TNF-induced cell death Arthritis, fever, colitis, amylopectinosis 
Disabling pansclerotic morphea of childhood STAT4 AD GOF 620443 Low CD4 T cells Unstimulated fibroblasts produce high levels of IL-6 Skin sclerosis, poor wound healing, joint contractures, mucosal ulcerations 
DiseaseGenetic defectInheritanceOMIMAffected cellsFunctional defectAssociated features
2. Defects affecting the inflammasome 
Familial Mediterranean fever (FMF) MEFV** AR LOF 249100 Mature granulocytes, cytokine-activated monocytes Increased pyrin inflammasome-mediated induction of IL-1β Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease, SAA amyloidosis 
AD 134610 Mature granulocytes, cytokine-activated monocytes Usually, M694del variant. Other missense variants in the B-Box and CC domains cause constitutive pyrin activation 
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia, and hypercalprotectinemia PSTPIP1 AD 604416 PMNs, monocytes Activation of the pyrin inflammasome; high production of IL-1 and IL-18 cytokines; interferon signature Destructive arthritis, inflammatory skin rash, myositis 
Mevalonate kinase deficiency (hyper-IgD syndrome/HIDS) MVK AR 260920 Somatic and hematopoietic Defect in production of isoprenoids, which are synthesized via mevalonate pathway and play a role in regulation of many signaling pathways Periodic fever and leukocytosis with usually high IgD levels 
PMVK deficiency PMVK AR NA Leukocytes Similar to MVK deficiency, increased IL-1β Recurrent fever episodes, arthritis, and cytopenia 
Muckle–Wells syndrome NLRP3** AD GOF 191900 PMNs Monocytes Activation of cryopyrin inflammasome results in increased production of IL-1/IL-18 cytokines and cell death via pyroptosis Urticaria, SNHL, SAA amyloidosis 
Familial cold autoinflammatory syndrome 1 AD GOF 120100 PMNs, monocytes Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure 
Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA) AD GOF 607115 PMNs, chondrocytes Neonatal-onset rash, chronic meningitis, and arthropathy with fever and inflammation 
Keratitis fugax hereditaria associated with c.61G>C
NLRP3 		AD GOF 606416  Episodic conjunctival injection, ocular pain, photophobia, foreign body sensation, and excessive tearing during acute attacks. Corneal opacities during attacks 
Familial cold autoinflammatory syndrome 2 NLRP12 AD GOF 611762 PMNs, monocytes Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure 
NLRC4-MAS (macrophage-activating syndrome) NLRC4 AD GOF 616050 PMNs, monocytes, macrophages, intestinal epithelial cells GOF mutation in NLRC4 results in elevated secretion of IL-1β and IL-18, as well as macrophage activation Severe enterocolitis and macrophage activation syndrome 
Familial cold autoinflammatory syndrome 4 616115 
APLAID or autoinflammation, antibody deficiency, and immune dysregulation Missense variants
PLCG2
Small intragenic deletions 		AD GOF/LOF 614878 B cells, NK, mast cells Mutations affect the autoinhibitory domains and activate NF-κB and MAPK pathways Cold urticaria hypogammaglobulinemia, impaired humoral immunity, autoantibodies, autoinflammation, granulomas 
PLAID or familial cold autoinflammatory syndrome 3 614468 
Autoinflammation with arthritis and dyskeratosis (AIADK; NLRP1 deficiency) NLRP1 AR 617388 Keratinocytes and leukocytes Systemic elevation of IL-18, IL-1β, caspase 1, suggesting activation of NLRP1 inflammasome Dyskeratosis, autoimmunity, and arthritis 
NLRP1 GOF NLRP1 AD GOF 615225 Keratinocytes Spontaneous production of IL-1β and IL-18 cytokines in keratinocytes Palmoplantar carcinoma, corneal scarring; recurrent respiratory papillomatosis 
Autoinflammation with episodic fever and lymphadenopathy/cleavage-resistant RIPK1-induced autoinflammatory syndrome/CRIA RIPK1 AD 618852 Leukocytes and fibroblasts TNF-induced cell death via apoptosis and necroptosis Long-lasting fever episodes, lymphadenopathy, splenohepatomegaly, ulcers, arthralgia, GI features 
Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) LPIN2 AR 609628 Neutrophils, bone marrow cells Dysregulation in cholesterol synthesis impairs the negative regulation of NLRP3 in macrophages resulting in high production of IL-1 Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders 
3. Non-inflammasome–related conditions 
TNF receptor–associated periodic syndrome (TRAPS) TNFRSF1A** AD 142680 PMNs, monocytes Mutations in the extracellular domain of 55-kD TNF receptor cause protein misfolding and intracellular receptor retention resulting in upregulation of ER stress Recurrent fever, serositis, rash, and ocular or joint inflammation 
Blau syndrome NOD2** AD 186580 Monocytes, intestinal epithelial cells Mutations in nucleotide binding site of CARD15 result in constitutive activation of NOD2 noadosome nd upregulation of NF-κB signaling Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies; 30% develop Crohn’s colitis 
ADAM17 deficiency ADAM17 AR 614328 Leukocytes and epithelial cells Defective TNF-α production Early-onset diarrhea and skin lesions 
DIRA (deficiency of the interleukin-1 receptor antagonist) IL1RN AR 612852 PMNs, monocytes Mutations in the IL-1 receptor antagonist allow unopposed action of IL-1α and IL-1β Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis 
Loss of IL-1R1 sensitivity to IL-Ra (LIRSA/CRMO3) (1 patient) IL-1R1 AD 259680 T cells and B cells Activated myeloid cells. Loss of IL-1R1 biding to endogenous IL-Ra Arthritis, osteolytic/sclerotic bone lesions, poor growth, no rash, no fever 
DITRA (deficiency of IL-36 receptor antagonist) IL36RN AR 614204 Keratinocytes, leukocytes Mutations in the IL-36 receptor antagonist allow unopposed action of IL-1α and IL-1β Pustular psoriasis 
Histiocytosis-lymphadenopathy plus syndrome/H syndrome (ENT3) SLC29A3 AR 602782 Leukocytes, histiocytes Defect in nucleoside transport functions of hENT3 leads to histiocytic infiltration of numerous organs Hyperpigmentation hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally hyperglycemia/diabetes mellitus 
CAMPS (CARD14-mediated psoriasis) CARD14 AD 602723 Mainly in keratinocytes Mutations in CARD14 activate the NF-κB pathway and production of IL-8 Psoriasis 
Cherubism SH3BP2 AD 118400 Stromal cells, bone cells Hyperactivated macrophages and osteoclasts, increased NF-κB signaling Bone degeneration in jaws 
PRAAS-CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) PSMB8* AR and AD 256040 Keratinocytes, B-cell adipose cells Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature Contractures, panniculitis, ICC, fevers 
PSMG2 AR 609702 Lymphocytes Panniculitis, lipodystrophy, autoimmune hemolytic anemia 
PSMB10 AR 619175 Lymphocytes Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature Periorbital and hand–foot annular rash (neutrophilic dermatosis), microcytic anemia, long slender fingers, hepatomegaly and splenomegaly 
PSMB9 AR or digenic or DN 617591 Lymphocytes Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature  
PSMB4 AR or digenic 617591 Lymphocytes Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature Panniculitis, lipodystrophy, autoimmune hemolytic anemia 
PRAID POMP AD 618048 Lymphocytes Increased accumulation of ubiquitinated proteins and ER stress with increased IFN signaling mediated by increased PKR signaling CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)/ interstitial lung disease in one patient, liver disease in one patient. Recurrent and opportunistic infections. Low CD8 T cells, skewing toward naïve T cells. Low B cells and positive autoantibodies 
PSMB9 deficiency (G156D) PSMB9 AD (DN LOF) 617591 Leukocytes (mild pancytopenia) Decreased protein expression and reduced proteasome activities. Elevated levels of inflammatory cytokines (IL-6, IL-18, IP-10, IFN-α), liver enzymes in blood and CSF (IFN-α), hyperactivation of IFN-α, pSTAT1 Severe autoinflammatory phenotype (neonatal-onset fever, skin rash, myositis, severe pulmonary hypertension, basal ganglia calcification), periodic inflammatory exacerbation; immunodeficiency. Partial phenocopy of PRAAS 
Autoinflammation with neurodevelopmental disease PSMD12 AR 617516 CNS, lymphocytes ↑ peripheral blood type I IFN gene signature has been reported for some patients Intellectual disability, developmental delay, urticarial skin rash, elevated interferon signature 
COPA syndrome COPA AD 601924 PMN and tissue-specific cells Defective intracellular transport via the coat protein complex I (COPI). Exacerbated STING-mediated type I interferon response Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production 
Otulipenia/ORAS OTULIN AR/AD 615712 Leukocytes, fibroblasts Increase LUBAC induction of NF-κB and interferon activation leading to high proinflammatory cytokine levels. Increase in TNF-induced cell death Fever, diarrhea, skin abscesses, panniculitis 
Dominant negative OTULIN-related autoinflammatory syndrome (3 patients) OTULIN AD 615712 Lymphocytes and fibroblasts Decreased catalytic activity, accumulation of linear ubiquitin chains, increased TNF-induced cell death, Spontaneous systemic inflammation 
OTULIN haploinsufficiency OTULIN AD 615712 Epithelial cells Increased activity of caveolin-1 stabilizes ADAM10 receptor for S. aureus toxin Susceptibility to S. aureus infections in epithelial cells 
Haploinsufficiency of A20/HA20 TNFAIP3 AD 616744 Lymphocytes Defective inhibition of NF-κB signaling pathway Arthralgia, mucosal ulcers, ocular inflammation 
AP1S3 deficiency AP1S3 AR 615781 Keratinocytes Disrupted TLR3 translocation Pustular psoriasis 
ALPI deficiency ALPI AR 171740 Intestinal epithelial cells Deficient inhibition of LPS in intestine Inflammatory bowel disease 
TRIM22 TRIM22 AR 606559 Macrophages, intestinal epithelial cells Granulomatous colitis Inflammatory bowel disease 
T-cell lymphoma subcutaneous panniculitis-like (TIM3 deficiency) HAVCR2 AR 618398 Leukocytes Increased inflammasome activity due to defective checkpoint signaling Panniculitis, HLH, polyclonal cutaneous T-cell infiltrates or T-cell lymphoma 
C2orf69 deficiency (28 patients) C2orf69 AR 619423 Outer mitochondrial membrane of all cells C2orf69 regulates mitochondrial function; protein deficiency causes respiratory chain defects Early-onset severe autoinflammation disorder, often fatal. Global developmental delay, with recurrent seizures, muscle weakness due to glycogen deposits 
SYK GOF SYK AD GOF 619381 Lymphocytes, osteoclasts Increased SYK phosphorylation, enhanced NF-κB, JNK, and ERK signaling. Mutated T cells are hypersensitive to stimulation and produce various proinflammatory chemokines and cytokines (IL-17, IL-22, TNF, IFN-γ) Recurrent infections, multi-organ inflammation/inflammatory disease (gut, skin, CNS, lung, liver), B-cell lymphoma reported in 2 pts 
HCK GOF HCK AD GOF 620296 Lymphocytes Increased kinase activity of HCK mutant in vitro; ↑ production of inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), ROS Cutaneous vasculitis, inflammatory leukocyte infiltration of the lungs (pulmonary fibrosis) and skin, anemia, hepatosplenomegaly 
NEMO exon 5 deletion IKBKG XL 301081 Leukocytes Mutant NEMO lacks exon 5 (NEMO-Dex5), fails to bind TBK1; NEMO-Dex5 stabilized IKKi, strong NF-κB, and interferon gene expression signatures Fever, skin rash, systemic autoinflammation, infections, CNS involvement, panniculitis, uveitis, hepatosplenomegaly, ectodermal dysplasia 
TBK1 deficiency TBK1 AR 620880 Leukocytes Autoinflammation driven by TNF-induced RIPK1-dependent cell death Chronic systemic autoinflammation (polyarthritis, vasculitis, rash); delayed neurocognitive development 
Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) ALPK1 AD 614979 Lymphocytes Immune activation with increased NF-κB signaling, STAT1 phosphorylation, and interferon gene expression signature Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache, fever, arthritis, colitis, dental abnormalities 
LYN GOF
Systemic autoinflammatory disease with vasculitis, SAIDV 		LYN AD GOF 620376 Endothelial cells and neutrophils Activated endothelial cells, constitutively active neutrophils Diffuse purpuric rash/atopic dermatitis, fever, hepatosplenomegaly, liver fibrosis/calcifications, arthritis, periorbital edema, respiratory insufficiency, colitis, poor growth 
SHARPIN deficiency SHARPIN AR 620795 Impaired development of germinal centers in secondary lymphoid organs, low CD20+cells, increased memory B cells Defect in LUBAC function, attenuated canonical NF-κB responses, increased TNF-induced cell death Arthritis, fever, colitis, amylopectinosis 
Disabling pansclerotic morphea of childhood STAT4 AD GOF 620443 Low CD4 T cells Unstimulated fibroblasts produce high levels of IL-6 Skin sclerosis, poor wound healing, joint contractures, mucosal ulcerations 

IFN, interferon; HSM, hepatosplenomegaly; CSF, cerebrospinal fluid; SLE, systemic lupus erythematosus; TORCH, toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections; SNHL, sensorineural hearing loss; AGS, Aicardi-Goutières syndrome; BSN, bilateral striatal necrosis; FCL, familial chilblain lupus; ICC, intracranial calcification; IFN, interferon type I; pDCs, plasmacytoid dendritic cells; SP, spastic paraparesis; SMS, Singleton–Merten syndrome; ss, single-stranded; ADA, adenosine deaminase; CNS, central nervous system; IBD, inflammatory bowel disease; autoAbs, autoantibodies.

* variants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic (PSMB4), digenic (PSMA3/PSMB8, PSMB9/PSMB4, PSMB4/PSMB8), and AD monogenic (POMP) models (119). Only G156D mutation in PSMB9 has been shown to cause an autoinflammatory phenotype with immunodeficiency in patients and mouse model (120).

Total number of disorders in Table 7: 69.

New IEIs: 11, STAT4 GOF, PMVK, ALPK1, LYN GOF, SHARPIN, LSM11, RNU71, ARF1, OTULIN (two new entries), and RELA (84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94).

** depicts that somatic mutations mimicking the germline disorder have been described for this gene.

a

RELA previously described as causing combined immunodeficiency a second entry included here as DN mutations are associated with an inflammatory phenotype with different mechanism of disease. OTULIN is repeated three times as different mechanisms of disease give rise to different phenotypes. NLRP1 is also repeated twice as AR and AD forms result in different phenotypes.

View large
Table 8.

Complement deficiencies

DiseaseGenetic defectInheritanceGene OMIMLaboratory featuresAssociated features
Complement deficiencies 
C1q deficiency due to defects C1QA AR 120550 Absent CH50 hemolytic activity, defective activation of the classical pathway, diminished clearance of apoptotic cells SLE, infections with encapsulated organisms 
C1QB AR 120570 
C1QC AR 120575 
C1r deficiency C1R AR 613785 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, Ehlers–Danlos phenotype 
C1r Periodontal Ehlers–Danlos C1R AD GOF 613785 Normal CH50 Hyperpigmentation, skin fragility 
C1s deficiency C1S AR 613785 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, Ehlers–Danlos phenotype 
C1s Periodontal Ehlers–Danlos C1S AD GOF 613785 Normal CH50 Hyperpigmentation, skin fragility 
Complete C4 deficiency C4A+C4B AR 120810 Absent CH50 hemolytic activity, defective activation of the classical pathway, complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B SLE, infections with encapsulated organisms, partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense 
C2 deficiency C2 AR 217000 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, atherosclerosis 
C3 deficiency (LOF) C3 AR 120700 Absent CH50 and AH50 hemolytic activity, defective opsonization, defective humoral immune response Infections, glomerulonephritis, atypical hemolytic–uremic syndrome with GOF mutations 
C3 GOF C3 AD GOF 120700 Increased activation of complement Atypical hemolytic–uremic syndrome 
C5 deficiency C5 AR 120900 Absent CH50 and AH50 hemolytic activity
Defective bactericidal activity 		Disseminated neisserial infections 
C6 deficiency C6 AR 217050 Absent CH50 and AH50 hemolytic activity, defective bactericidal activity 
C7 deficiency C7 AR 217070 
C8α deficiency C8A AR 120950 
C8γ deficiency C8G AR 120930 
C8β deficiency C8B AR 120960 
C9 deficiency C9 AR 120940 Reduced CH50 and AP50 hemolytic activity, deficient bactericidal activity Mild susceptibility to disseminated neisserial infections 
MASP2 deficiency MASP2 AR 605102 Deficient activation of the lectin activation pathway Pyogenic infections, inflammatory lung disease, autoimmunity 
Ficolin-3 deficiency FCN3 AR 604973 Absence of complement activation by the ficolin-3 pathway Respiratory infections, abscesses 
C1 inhibitor deficiency SERPING1 AD/AR 606860 Spontaneous activation of the complement pathway with consumption of C4/C2, spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen Hereditary angioedema 
Factor B GOF CFB AD GOF 612924 GOF mutation with increased spontaneous AH50 Atypical hemolytic–uremic syndrome 
Factor B deficiency CFB AR 615561 Deficient activation of the alternative pathway Infections with encapsulated organisms 
Factor D deficiency CFD AR 134350 Absent AH50 hemolytic activity Neisserial infections 
Properdin deficiency CFP XL 300383 Absent AH50 hemolytic activity Neisserial infections 
Factor I deficiency CFI AR 217030 Spontaneous activation of the alternative complement pathway with consumption of C3 Infections, disseminated neisserial infections, atypical hemolytic–uremic syndrome, preeclampsia 
Factor H deficiency CFH AR or AD 134370 Spontaneous activation of the alternative complement pathway with consumption of C3 
Factor H–related protein deficiencies CFHR1 AR or AD 134371 Normal CH50, AH50, autoantibodies to factor H, linked deletions of one or more CFHR genes lead to susceptibility to autoantibody-mediated aHUS Older onset atypical hemolytic–uremic syndrome, disseminated neisserial infections 
CFHR2 600889 
CFHR3 605336 
CFHR4 605337 
CFHR5 608593 
Thrombomodulin deficiency THBD AD 188040 Normal CH50, AH50 Atypical hemolytic–uremic syndrome 
Membrane cofactor protein (CD46) deficiency CD46 AD/AR 120920 Inhibitor of complement alternate pathway, decreased C3b binding Atypical hemolytic–uremic syndrome, infections, preeclampsia 
Membrane attack complex inhibitor (CD59) deficiency CD59 AR 107271 Erythrocytes highly susceptible to complement-mediated lysis Hemolytic anemia, polyneuropathy 
CD55 deficiency (CHAPLE disease) CD55 AR 125240 Hyperactivation of complement on endothelium Protein losing enteropathy, thrombosis 
DiseaseGenetic defectInheritanceGene OMIMLaboratory featuresAssociated features
Complement deficiencies 
C1q deficiency due to defects C1QA AR 120550 Absent CH50 hemolytic activity, defective activation of the classical pathway, diminished clearance of apoptotic cells SLE, infections with encapsulated organisms 
C1QB AR 120570 
C1QC AR 120575 
C1r deficiency C1R AR 613785 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, Ehlers–Danlos phenotype 
C1r Periodontal Ehlers–Danlos C1R AD GOF 613785 Normal CH50 Hyperpigmentation, skin fragility 
C1s deficiency C1S AR 613785 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, Ehlers–Danlos phenotype 
C1s Periodontal Ehlers–Danlos C1S AD GOF 613785 Normal CH50 Hyperpigmentation, skin fragility 
Complete C4 deficiency C4A+C4B AR 120810 Absent CH50 hemolytic activity, defective activation of the classical pathway, complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B SLE, infections with encapsulated organisms, partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense 
C2 deficiency C2 AR 217000 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, atherosclerosis 
C3 deficiency (LOF) C3 AR 120700 Absent CH50 and AH50 hemolytic activity, defective opsonization, defective humoral immune response Infections, glomerulonephritis, atypical hemolytic–uremic syndrome with GOF mutations 
C3 GOF C3 AD GOF 120700 Increased activation of complement Atypical hemolytic–uremic syndrome 
C5 deficiency C5 AR 120900 Absent CH50 and AH50 hemolytic activity
Defective bactericidal activity 		Disseminated neisserial infections 
C6 deficiency C6 AR 217050 Absent CH50 and AH50 hemolytic activity, defective bactericidal activity 
C7 deficiency C7 AR 217070 
C8α deficiency C8A AR 120950 
C8γ deficiency C8G AR 120930 
C8β deficiency C8B AR 120960 
C9 deficiency C9 AR 120940 Reduced CH50 and AP50 hemolytic activity, deficient bactericidal activity Mild susceptibility to disseminated neisserial infections 
MASP2 deficiency MASP2 AR 605102 Deficient activation of the lectin activation pathway Pyogenic infections, inflammatory lung disease, autoimmunity 
Ficolin-3 deficiency FCN3 AR 604973 Absence of complement activation by the ficolin-3 pathway Respiratory infections, abscesses 
C1 inhibitor deficiency SERPING1 AD/AR 606860 Spontaneous activation of the complement pathway with consumption of C4/C2, spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen Hereditary angioedema 
Factor B GOF CFB AD GOF 612924 GOF mutation with increased spontaneous AH50 Atypical hemolytic–uremic syndrome 
Factor B deficiency CFB AR 615561 Deficient activation of the alternative pathway Infections with encapsulated organisms 
Factor D deficiency CFD AR 134350 Absent AH50 hemolytic activity Neisserial infections 
Properdin deficiency CFP XL 300383 Absent AH50 hemolytic activity Neisserial infections 
Factor I deficiency CFI AR 217030 Spontaneous activation of the alternative complement pathway with consumption of C3 Infections, disseminated neisserial infections, atypical hemolytic–uremic syndrome, preeclampsia 
Factor H deficiency CFH AR or AD 134370 Spontaneous activation of the alternative complement pathway with consumption of C3 
Factor H–related protein deficiencies CFHR1 AR or AD 134371 Normal CH50, AH50, autoantibodies to factor H, linked deletions of one or more CFHR genes lead to susceptibility to autoantibody-mediated aHUS Older onset atypical hemolytic–uremic syndrome, disseminated neisserial infections 
CFHR2 600889 
CFHR3 605336 
CFHR4 605337 
CFHR5 608593 
Thrombomodulin deficiency THBD AD 188040 Normal CH50, AH50 Atypical hemolytic–uremic syndrome 
Membrane cofactor protein (CD46) deficiency CD46 AD/AR 120920 Inhibitor of complement alternate pathway, decreased C3b binding Atypical hemolytic–uremic syndrome, infections, preeclampsia 
Membrane attack complex inhibitor (CD59) deficiency CD59 AR 107271 Erythrocytes highly susceptible to complement-mediated lysis Hemolytic anemia, polyneuropathy 
CD55 deficiency (CHAPLE disease) CD55 AR 125240 Hyperactivation of complement on endothelium Protein losing enteropathy, thrombosis 

MAC, membrane attack complex; SLE, systemic lupus erythematosus.

Total number of mutant genes in Table 8: 36.

New disorders: None.

View large
Table 9.

Bone marrow failure

DiseaseGenetic defectInheritanceGene OMIMT cellsB cellsOther affected cellsAssociated featuresMajor categorySubcategory
1. Bone marrow failure 
Fanconi anemia type A FANCA AR 227650 Normal to low Normal to low HSC Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage Bone marrow failure with immune deficiency Fanconi anemia 
Fanconi anemia type B FANCB XLR 300514 
Fanconi anemia type C FANCC AR 227645 
Fanconi anemia type D1 BRCA2 AR 605724 
Fanconi anemia type D2 FANCD2 AR 227646 
Fanconi anemia type E FANCE AR 600901 
Fanconi anemia type F FANCF AR 603467 
Fanconi anemia type G FANCG/XRCC9 AR 614082 
Fanconi anemia type I FANCI AR 609053 
Fanconi anemia type J BRIP1 AR 609054 
Fanconi anemia type L FANCL AR 614083 
Fanconi anemia type M FANCM AR 618096 
Fanconi anemia type N PALB2 AR 610832 
Fanconi anemia type O RAD51C AR 613390 
Fanconi anemia type P SLX4 AR 613951 
Fanconi anemia type Q ERCC4 AR 615272 
Fanconi anemia type R RAD51 AR 617244 
Fanconi anemia type S BRCA1 AR 617883 
Fanconi anemia type T UBE2T AR 616435 
Fanconi anemia type U XRCC2 AR 617247 
Fanconi anemia type V MAD2L2 AR 617243 
Fanconi anemia type W RFWD3 AR 617784 
MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy) SAMD9 AD GOF 617053 Not reported Not reported HSC, myeloid cells Intrauterine growth retardation, gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen 
Ataxia–pancytopenia syndrome SAMD9L AD GOF 611170 Normal Low HSC, myeloid cells MDS, neurological features 
DKCX1 DKC1 XL 305000 Normal to low Normal to low HSC Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay  Dyskeratosis congenita 
DKCA1 TERC AD 127550 
DKCA2 TERT AD/AR 187270 
DKCA3 TINF2 AD 604319 
DKCA4 RTEL1 AD 616373 
DKCA5 TINF2 AD 268130 
DKCA6 ACD AD 616553 
DKCB1 NOP10/NOLA3 AR 224230 
DKCB2 NHP2/NOLA2 AR 613987 
DKCB3 WRAP53 AR 613988 
DKCB4 TERT AR 613989 
DKCB5 RTEL1 AR 615190 Low Nail dystrophy, leukoplakia, bone marrow failure, severe B-cell immunodeficiency, intrauterine growth retardation, growth retardation, microcephaly, cerebellar hypoplasia, and esophageal dysfunction 
DKCB6 PARN AR 616353 Normal to low Developmental delay, microcephaly, and cerebellar hypoplasia 
DKCB7 ACD AR 616553 Normal to low Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay 
BMFS1 (SRP72-deficiency) SRP72 AD 602122 NA NA  Bone marrow failure and congenital nerve deafness 
BMFS2 ERCC6L2 AR 615667 NA NA Bone marrow failure, learning difficulties, microcephaly 
BMFS5 TP53 AD 618165 NA Low B Erythroid hypoplasia, B-cell deficiency 
Coats plus syndrome STN1 AR 613129 Normal Normal Intrauterine growth retardation, premature aging, pancytopenia, hypocellular bone marrow, gastrointestinal hemorrhage due to vascular ectasia, intracranial calcification, abnormal telomeres 
CTC1 AR 617053 Not reported Not reported 
MECOM deficiency MECOM AD 616738 Not reported B-cell deficiency  Bone marrow failure, thrombocytopenia/pancytopenia, radioulnar synostosis, clinodactyly, cardiac, and renal malformations   
Dyskeratosis congenita, Høyeraal–Hreidarsson syndrome DCLRE1B AR 620133 Normal to low,
reduced
CD45RA 		B-cell deficiency Low neutrophils in n:1 Early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation   
BMF, macrocytosis, leukemia DUT AR 620044 NA NA HSC, stromal cells Diabetes, bone marrow failure BMF  
Nijmegen breakage syndrome–like disorder RAD50 AR 613078 Low T-cell counts, normal T-cell
proportions and proliferation 		B-cell deficiency  Microcephaly, mental retardation, bird-like face, short stature Progressive BMF and immunodeficiency  
DiseaseGenetic defectInheritanceGene OMIMT cellsB cellsOther affected cellsAssociated featuresMajor categorySubcategory
1. Bone marrow failure 
Fanconi anemia type A FANCA AR 227650 Normal to low Normal to low HSC Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage Bone marrow failure with immune deficiency Fanconi anemia 
Fanconi anemia type B FANCB XLR 300514 
Fanconi anemia type C FANCC AR 227645 
Fanconi anemia type D1 BRCA2 AR 605724 
Fanconi anemia type D2 FANCD2 AR 227646 
Fanconi anemia type E FANCE AR 600901 
Fanconi anemia type F FANCF AR 603467 
Fanconi anemia type G FANCG/XRCC9 AR 614082 
Fanconi anemia type I FANCI AR 609053 
Fanconi anemia type J BRIP1 AR 609054 
Fanconi anemia type L FANCL AR 614083 
Fanconi anemia type M FANCM AR 618096 
Fanconi anemia type N PALB2 AR 610832 
Fanconi anemia type O RAD51C AR 613390 
Fanconi anemia type P SLX4 AR 613951 
Fanconi anemia type Q ERCC4 AR 615272 
Fanconi anemia type R RAD51 AR 617244 
Fanconi anemia type S BRCA1 AR 617883 
Fanconi anemia type T UBE2T AR 616435 
Fanconi anemia type U XRCC2 AR 617247 
Fanconi anemia type V MAD2L2 AR 617243 
Fanconi anemia type W RFWD3 AR 617784 
MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy) SAMD9 AD GOF 617053 Not reported Not reported HSC, myeloid cells Intrauterine growth retardation, gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen 
Ataxia–pancytopenia syndrome SAMD9L AD GOF 611170 Normal Low HSC, myeloid cells MDS, neurological features 
DKCX1 DKC1 XL 305000 Normal to low Normal to low HSC Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay  Dyskeratosis congenita 
DKCA1 TERC AD 127550 
DKCA2 TERT AD/AR 187270 
DKCA3 TINF2 AD 604319 
DKCA4 RTEL1 AD 616373 
DKCA5 TINF2 AD 268130 
DKCA6 ACD AD 616553 
DKCB1 NOP10/NOLA3 AR 224230 
DKCB2 NHP2/NOLA2 AR 613987 
DKCB3 WRAP53 AR 613988 
DKCB4 TERT AR 613989 
DKCB5 RTEL1 AR 615190 Low Nail dystrophy, leukoplakia, bone marrow failure, severe B-cell immunodeficiency, intrauterine growth retardation, growth retardation, microcephaly, cerebellar hypoplasia, and esophageal dysfunction 
DKCB6 PARN AR 616353 Normal to low Developmental delay, microcephaly, and cerebellar hypoplasia 
DKCB7 ACD AR 616553 Normal to low Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay 
BMFS1 (SRP72-deficiency) SRP72 AD 602122 NA NA  Bone marrow failure and congenital nerve deafness 
BMFS2 ERCC6L2 AR 615667 NA NA Bone marrow failure, learning difficulties, microcephaly 
BMFS5 TP53 AD 618165 NA Low B Erythroid hypoplasia, B-cell deficiency 
Coats plus syndrome STN1 AR 613129 Normal Normal Intrauterine growth retardation, premature aging, pancytopenia, hypocellular bone marrow, gastrointestinal hemorrhage due to vascular ectasia, intracranial calcification, abnormal telomeres 
CTC1 AR 617053 Not reported Not reported 
MECOM deficiency MECOM AD 616738 Not reported B-cell deficiency  Bone marrow failure, thrombocytopenia/pancytopenia, radioulnar synostosis, clinodactyly, cardiac, and renal malformations   
Dyskeratosis congenita, Høyeraal–Hreidarsson syndrome DCLRE1B AR 620133 Normal to low,
reduced
CD45RA 		B-cell deficiency Low neutrophils in n:1 Early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation   
BMF, macrocytosis, leukemia DUT AR 620044 NA NA HSC, stromal cells Diabetes, bone marrow failure BMF  
Nijmegen breakage syndrome–like disorder RAD50 AR 613078 Low T-cell counts, normal T-cell
proportions and proliferation 		B-cell deficiency  Microcephaly, mental retardation, bird-like face, short stature Progressive BMF and immunodeficiency  

HSC, hematopoietic stem cell; NK, natural killer; CNS, central nervous system; GI, gastrointestinal, MDS, myelodysplastic syndrome; DKCX: X-linked dyskeratosis congenital; DKCA, autosomal dominant dyskeratosis congenita; DKCB, autosomal recessive dyskeratosis congenita; BMFS, bone marrow failure syndrome.

Total number of mutant genes in Table 9: 47.

New IEIs: 3, DCLRE1B (Apollo), DUT, and RAD50 (99, 121, 122).

View large
Table 10.

Phenocopies of IEIs associated with autoantibodies or somatic variants

DiseaseGenetic defect/presumed pathogenesisCirculating T cellsCirculating B cellsSerum IgAssociated features/similar IEI
1. Phenocopies of IEIs 
Associated with somatic mutations 
Autoimmune lymphoproliferative syndrome (ALPS-SFAS) Somatic mutation in TNFRSF6 Increased CD4−CD8−double-negative (DN) αβ T cells Normal, but increased, number of CD5+ B cells Normal or increased Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis/ALPS-FAS (=ALPS) 
RAS-associated autoimmune leukoproliferative disease (RALD) Somatic mutation in KRAS (GOF) Normal B-cell lymphocytosis Normal or increased Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like 
RAS-associated autoimmune leukoproliferative disease (RALD) Somatic mutation in NRAS (GOF) Increased CD4−CD8− DN T αβ cells Lymphocytosis Normal or increased Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like 
Cryopyrinopathy, (Muckle–Wells/CINCA/NOMID-like syndrome)a Somatic mutation in NLRP3 Normal Normal Normal Urticaria-like rash, arthropathy, neurological signs 
Hypereosinophilic syndrome due to somatic mutations in STAT5b Somatic GOF mutation in STAT5B Normal Normal Normal Eosinophilia, atopic dermatitis, urticarial rash, diarrhea 
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome Somatic GOF mutation in UBA1 (XL) Lymphopenia Reduced Normal Late-onset treatment-refractory inflammatory syndrome (fevers, neutrophilic dermatosis, macrocytic anemia, dysplastic bone marrow, interstitial nephritis, chondritis, vasculitis) 
TLR8 GOF Somatic GOF mutation in TLR8 ↑ (mild) CD4+, CD8+ T cells, effector/memory subsets; ↓NK cells Normal B cells/subsets,
↓ pDCs 		Normal/lo IgG, ↑ IgM/IgA Severe cytopenias, hepatosplenomegaly, lymphadenopathy; recurrent infections; hypocellular bone marrow, elevated proinflammatory serum cytokines 
JAK1 GOF (S703I)a Somatic GOF mutation in JAK1 Upregulated STAT3 phosphorylation in T cells Upregulated STAT6 phosphorylation  Asymmetric pustular rash (inflammatory linear verrucous epidermal nevus) chronic GI tract inflammation, eosinophilic colitis. Peripheral eosinophilia. Membranous glomerulonephritis, asthma 
Associated with autoantibodies 
Chronic mucocutaneous candidiasis AutoAb to IL-17A and/or IL-17F Normal Normal Normal Endocrinopathy, chronic mucocutaneous candidiasis/CMC 
Adult-onset immunodeficiency with susceptibility to environmental mycobacteria AutoAb to IFN-γ Decreased naïve T cells Normal Normal Susceptibility to intramacrophagic pathogens (mycobacteria, fungi, Talaromyces marneffei, Salmonella), VZV infections/MSMD, or CID 
Recurrent staphylococcal skin infection AutoAb to IL-6 Normal Low Normal Staphylococcal infections/STAT3 deficiency 
Pulmonary alveolar proteinosis AutoAb to GM-CSF Normal Normal Normal Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency 
Acquired angioedema AutoAb to C1 inhibitor Normal Normal Normal Angioedema/C1 INH deficiency (hereditary angioedema) 
Atypical hemolytic uremic syndrome AutoAb to complement factor H (CFH) Normal Normal Normal aHUS = spontaneous activation of the alternative complement pathway 
Thymoma with hypogammaglobulinemia (Good’s syndrome) AutoAb to various cytokinesb including type I IFNs Decreased CD4+ T cells, increased CD8+ T cells No B cells Decreased Invasive bacterial, viral, or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea 
Critical viral infections AutoAb to type 1 IFNs (IFN-α, IFN-ω)    • Severe, life-threatening SARS-CoV-2 infection
• Critical/“breakthrough” COVID-19 pneumonia
• Adverse reactions to yellow fever YFV-17D live-attenuated viral vaccine
• Critical influenza pneumonia
• Critical Middle East respiratory syndrome (MERS) pneumonia
• West Nile virus (WNV) encephalitis 
Sporadic infectious mononucleosis and chronic EBV infection AutoAb to IL-27    Infectious mononucleosis, chronic EBV active infection/IL-27RA deficiency 
DiseaseGenetic defect/presumed pathogenesisCirculating T cellsCirculating B cellsSerum IgAssociated features/similar IEI
1. Phenocopies of IEIs 
Associated with somatic mutations 
Autoimmune lymphoproliferative syndrome (ALPS-SFAS) Somatic mutation in TNFRSF6 Increased CD4−CD8−double-negative (DN) αβ T cells Normal, but increased, number of CD5+ B cells Normal or increased Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis/ALPS-FAS (=ALPS) 
RAS-associated autoimmune leukoproliferative disease (RALD) Somatic mutation in KRAS (GOF) Normal B-cell lymphocytosis Normal or increased Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like 
RAS-associated autoimmune leukoproliferative disease (RALD) Somatic mutation in NRAS (GOF) Increased CD4−CD8− DN T αβ cells Lymphocytosis Normal or increased Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like 
Cryopyrinopathy, (Muckle–Wells/CINCA/NOMID-like syndrome)a Somatic mutation in NLRP3 Normal Normal Normal Urticaria-like rash, arthropathy, neurological signs 
Hypereosinophilic syndrome due to somatic mutations in STAT5b Somatic GOF mutation in STAT5B Normal Normal Normal Eosinophilia, atopic dermatitis, urticarial rash, diarrhea 
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome Somatic GOF mutation in UBA1 (XL) Lymphopenia Reduced Normal Late-onset treatment-refractory inflammatory syndrome (fevers, neutrophilic dermatosis, macrocytic anemia, dysplastic bone marrow, interstitial nephritis, chondritis, vasculitis) 
TLR8 GOF Somatic GOF mutation in TLR8 ↑ (mild) CD4+, CD8+ T cells, effector/memory subsets; ↓NK cells Normal B cells/subsets,
↓ pDCs 		Normal/lo IgG, ↑ IgM/IgA Severe cytopenias, hepatosplenomegaly, lymphadenopathy; recurrent infections; hypocellular bone marrow, elevated proinflammatory serum cytokines 
JAK1 GOF (S703I)a Somatic GOF mutation in JAK1 Upregulated STAT3 phosphorylation in T cells Upregulated STAT6 phosphorylation  Asymmetric pustular rash (inflammatory linear verrucous epidermal nevus) chronic GI tract inflammation, eosinophilic colitis. Peripheral eosinophilia. Membranous glomerulonephritis, asthma 
Associated with autoantibodies 
Chronic mucocutaneous candidiasis AutoAb to IL-17A and/or IL-17F Normal Normal Normal Endocrinopathy, chronic mucocutaneous candidiasis/CMC 
Adult-onset immunodeficiency with susceptibility to environmental mycobacteria AutoAb to IFN-γ Decreased naïve T cells Normal Normal Susceptibility to intramacrophagic pathogens (mycobacteria, fungi, Talaromyces marneffei, Salmonella), VZV infections/MSMD, or CID 
Recurrent staphylococcal skin infection AutoAb to IL-6 Normal Low Normal Staphylococcal infections/STAT3 deficiency 
Pulmonary alveolar proteinosis AutoAb to GM-CSF Normal Normal Normal Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency 
Acquired angioedema AutoAb to C1 inhibitor Normal Normal Normal Angioedema/C1 INH deficiency (hereditary angioedema) 
Atypical hemolytic uremic syndrome AutoAb to complement factor H (CFH) Normal Normal Normal aHUS = spontaneous activation of the alternative complement pathway 
Thymoma with hypogammaglobulinemia (Good’s syndrome) AutoAb to various cytokinesb including type I IFNs Decreased CD4+ T cells, increased CD8+ T cells No B cells Decreased Invasive bacterial, viral, or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea 
Critical viral infections AutoAb to type 1 IFNs (IFN-α, IFN-ω)    • Severe, life-threatening SARS-CoV-2 infection
• Critical/“breakthrough” COVID-19 pneumonia
• Adverse reactions to yellow fever YFV-17D live-attenuated viral vaccine
• Critical influenza pneumonia
• Critical Middle East respiratory syndrome (MERS) pneumonia
• West Nile virus (WNV) encephalitis 
Sporadic infectious mononucleosis and chronic EBV infection AutoAb to IL-27    Infectious mononucleosis, chronic EBV active infection/IL-27RA deficiency 

Abbreviations for all tables: XL, X-linked; AR, autosomal recessive; AD, autosomal dominant; LOF, loss of function; GOF, gain of function; PRCA, pure red cell aplasia; autoAb, autoantibody; aHUS, atypical hemolytic–uremic syndrome; ALPS, autoimmune lymphoproliferative syndrome; CID, combined immunodeficiency.

Total number of conditions for Table 10: 17 (8 due to somatic mutations; 9 due to autoantibodies).

New phenocopies: 2, 1 due to somatic mutation in JAK1 (100) and 1 due to autoantibodies against IL-27 (68). Antibodies against type I interferons previously described for patients with severe COVID-19 were now also described in patients with other severe viral infections; hence, this entry was modified to include SARS-CoV-2 breakthrough infections and others (123, 124).

a

Phenocopies of germline disease.

b

Autoantibodies against IL-23 were described in the context of thymoma (125).

View large
Figure 1.
Expanding universe of IEIs: 1980–2024. (A) Number of IEIs as reported in the indicated year. (B) Number of IEIs listed in each table of the IUIS IEI Committee 2024 Report. The numbers in each column correspond to the number of genes reported in the 2022 IUIS update (blue bars), the number of new genes for each table contained in this report (red bars), and the total number of genes for each table (black number). Note: the 17 conditions listed for Table 10 are either phenocopies of germline IEIs due to somatic variants or neutralizing autoantibodies.
View large Download slide

Expanding universe of IEIs: 1980–2024. (A) Number of IEIs as reported in the indicated year. (B) Number of IEIs listed in each table of the IUIS IEI Committee 2024 Report. The numbers in each column correspond to the number of genes reported in the 2022 IUIS update (blue bars), the number of new genes for each table contained in this report (red bars), and the total number of genes for each table (black number). Note: the 17 conditions listed for Table 10 are either phenocopies of germline IEIs due to somatic variants or neutralizing autoantibodies.

Figure 1.
Expanding universe of IEIs: 1980–2024. (A) Number of IEIs as reported in the indicated year. (B) Number of IEIs listed in each table of the IUIS IEI Committee 2024 Report. The numbers in each column correspond to the number of genes reported in the 2022 IUIS update (blue bars), the number of new genes for each table contained in this report (red bars), and the total number of genes for each table (black number). Note: the 17 conditions listed for Table 10 are either phenocopies of germline IEIs due to somatic variants or neutralizing autoantibodies.
View large Download slide

Expanding universe of IEIs: 1980–2024. (A) Number of IEIs as reported in the indicated year. (B) Number of IEIs listed in each table of the IUIS IEI Committee 2024 Report. The numbers in each column correspond to the number of genes reported in the 2022 IUIS update (blue bars), the number of new genes for each table contained in this report (red bars), and the total number of genes for each table (black number). Note: the 17 conditions listed for Table 10 are either phenocopies of germline IEIs due to somatic variants or neutralizing autoantibodies.

Close modal

The committee strives to publish an updated report every 2 years to consolidate advances and catalog current IEIs (4). A large array of genetic variants related to IEI has been reported recently. Rather than including every candidate gene published in the peer-reviewed scientific literature, the committee applies stringent criteria to classify gene defects as novel causes of IEIs (11). These criteria include the following:

  • (1)

    The candidate genotype is monogenic and is not found in individuals without the clinical phenotype (recognizing that some conditions have incomplete penetrance).

  • (2)

    Experimental studies establish that the genetic variant impairs, destroys, or alters expression or function of the gene product.

  • (3)

    The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, including—where possible—rescue of a functional defect (11).

These criteria can be met by the publication of multiple cases from unrelated families, including detailed immunological data; or publication of very few—even single—cases with compelling mechanistic data, often revealed from complementary studies in animal or cell culture models. With the number of genes and conditions growing, the committee also considers it essential that the immunological phenotype is described in-depth beyond the clinical phenotype. We also considered whether sufficient justification was provided to exclude alternative candidate gene variants identified in single cases, the depth of the clinical descriptions of the affected individuals, and the level of immune and functional characterization. It is important to consider that for specific diseases, even though at this point they fulfill the criteria to be included in these tables, building evidence may argue against disease causality. Indeed, stringent criteria are being developed to remove certain genes or inheritance modes from this list in the future.

This 2024 IUIS IEI update is intended as a follow-up resource for clinicians and researchers, and it can guide the design of panels used for targeted gene sequencing to facilitate clinical genetic diagnoses of IEI. Here, we summarize data on the genetic cause of 67 novel IEIs, and 2 phenocopies of IEI due to either autoantibodies (n = 1) or somatic mutations (n = 1), that have been assessed since the previous update (12). This increases the number of genes associated with IEI to 508, causing 559 conditions (Fig. 1 A). This includes four chromosomal deletion syndromes (22q11.2 deletion syndrome [DS], chromosome 11q DS, 10p13-p14DS [Table 2, subtables 3 and 9], and 14q 32 DS [Table 2, subtable 4]), as well as KRAS, NRAS, and UBA1, for which disease is only described due to somatic variants (Table 10). Given the rapid pace of discovery, the current update will likely be outdated by the time of its publication.

One gene, several phenotypes

For this update, IEIs are classified according to the predominant clinical presentation. However, patients with pathogenic mutations in specific IEI-associated genes may have clinical presentations that differ from the predominant clinical presentation under which they have been classified in this document, thereby expanding the phenotypic spectrum of disease. In this regard, some previously reported genes and IEIs have been reclassified into a different table after panel discussion. Nevertheless, it is important to stress that the disease-causing effect of a genetic variant cannot be excluded solely because the description of the classic phenotype in this table does not fit with the clinical presentation of a given patient. Indeed, the presenting phenotype of many IEIs is gradually expanding and this must be taken into careful consideration. One example of this is mutations in the WD40 domain of COPA causing COPA syndrome with arthritis and alveolar hemorrhages as the main clinical manifestations (13). However, patients with mutations in the C-terminal domain can have a wide spectrum of clinical manifestations including autoimmunity and neuroinflammation (14). It is therefore challenging to exclude pathogenicity of a novel variant, even if the phenotype is not typical for the described gene defect as the mechanism of disease and phenotype may differ based on the location of the variant. Furthermore, several IEIs may have incomplete penetrance (i.e., JAK1 GOF, PLCG2 LOF, NLRC4 GOF, PTPN2, among others) increasing complexity of genomic analysis, given that diseased individuals may have healthy family members carrying the same variant. Different factors may contribute to incomplete penetrance, and these are still not fully understood. Monoallelic expression has recently been identified as an important contributor to incomplete penetrance and should be taken into consideration (15).

Redefining or broadening of the clinical phenotype can also occur simply by the description of additional patients. Examples include AR MYD88 and IRAK4 deficiencies, which have been associated with susceptibility to invasive pyogenic bacterial infections, but recently have been found to cause severe viral infections (including coronaviruses and influenza) in some affected individuals (16). Alternatively, gene dose can impact disease phenotype and severity, in diseases that are classically described as AR disorders. An example of this phenomenon is mutations in RAG1, in which biallelic LOF mutations classically cause SCID, but patients with biallelic hypomorphic mutations can present later in life with combined immunodeficiency or milder immune dysregulation depending on residual RAG activity (17, 18). These findings challenge the assumption that IEIs are inevitably ultrarare and severe diseases affecting primarily children. Rather, they may include more common disorders that can present across the lifespan or even exclusively after exposure to specific microorganisms (19). Because of the expanding phenotypes, we have updated tables with less restrictive titles, and we foresee that current classifications will need to be reconsidered as the spectrum of disease associated with individual genes can be diverse and as several signaling pathways often illicit disease in a concerted action.

Clinically and phenotypically distinct IEI can arise due to variants in the same gene that have divergent molecular mechanisms such as LOF, GOF, and neomorphic or multimorphic function. Examples of this are mutations in IRF4, with one new entry causing AD combined immunodeficiency (Table 1, subtable 3) due to a mutation resulting in a neomorphic function (20) and two entries in Table 6, subtable 9, causing either Whipple disease by haploinsufficiency or antibody deficiency by another AD neomorphic variant (20, 21, 22). Similarly, CARD11 has three entries in three different tables as different inheritance patterns and pathogenic mechanisms lead to distinct phenotypes. OTULIN also appears three times—all in Table 7, subtable 3—due to distinct mechanisms of disease (heterozygous dominant negative or haploinsufficiency; AR LOF) that still manifest with similar clinical phenotypes. STAT1 and STAT3 have different entries in different tables because mutations in these genes lead to dramatically different phenotypes by GOF or LOF. This also emphasizes the crucial need to undertake in-depth in vitro functional validation of any novel variant considered to be potentially pathogenic. As a result, in this current update, >40 genes have more than one entry either in the same table or in different tables. Considering this complexity, counting IEI has become increasingly difficult. To improve clarity, for this version, we decided to count the number of monogenic IEI conditions and, separately, the number of genes causative of disease. If mutations in a gene cause disease with a similar phenotype yet follow an AR/AD inheritance pattern, they were counted as one condition (e.g., AD or AR LOF variants in AICDA, STAT1, or AIRE). If the diseases caused by a pathogenic variant in a single gene following AR/AD inheritance present as distinct phenotypes, they are counted as two different conditions (e.g., AD or AR variants in CARD11, PIK3R1; GOF or LOF variants in STAT1 or STAT3). With evolving genetic and pathophysiological insight, the number of IEI may change in the future as some conditions might be considered a spectrum of one disease rather than truly different conditions. As a result, comparing the numbers with previous versions would not be accurate as the criteria for counting are continuously evolving.

The discovery of novel IEI continues to demonstrate that distinct variants or zygosity in the same gene can cause disparate clinical conditions. In the current update, UNC93B1 is an example. Whereas AR UNC93B1 LOF was identified previously as an IEI underlying herpes simplex encephalitis, recent findings link heterozygous UNC93B1 GOF variants to childhood-onset systemic lupus erythematosus (SLE) (23, 24); furthermore, mouse models have revealed a gene dosage effect of Unc93b1 GOF variants (25).

Novel IEIs

Since the last update in 2022 (12), novel gene defects have been found for most categories of IEI, including novel causes of:

  • Combined immunodeficiencies: IRF4 (AD neomorphic); NFATC1, PRIM1, POLD3, NUDCD3 (AR LOF); and FOXI3, PSMB10 (AD LOF) (20, 26, 27, 28, 29, 30, 31, 32) (Table 1, subtable 1);

  • Combined immunodeficiencies with syndromic features: IKZF2 (dominant negative); GINS4, SLC19A1, SGPL1, FLT3L, ITPR3, RECQL4 (AR LOF); PTCRA (AR LOF/hypomorphic); SMAD3 (AD); and STAT6 (AD GOF) (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) (Table 2, subtable 1);

  • B-cell deficiencies, agammaglobulinemia or hypogammaglobulinemia PAX5, PI4KA, KARS1 (48, 49, 50) (all AR LOF; Table 3, subtable 1);

  • Immune dysregulation: CD274 (PDL1), CBLB, SH2B3, ARPC5, NFATC2, DOCK11, RHBDF2, LACC1, NBEAL2, IL27RA, TNFSF9, DPP9, GIMAP6 (AR LOF); ERN1, PTPN2 (AD LOF); TRAF3 (AD haploinsufficiency); and TLR7, UNC93B1, PLCG1 (AD GOF) (23, 25, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72) (Table 4, subtable 1);

  • Neutropenia: DBF4, SRP19, SRPRA, CCR2 (73, 74, 75) (all AR LOF; Table 5, subtable 1);

  • Innate immune defects resulting in susceptibility to mycobacterial/bacterial (IRF1, MCTS1 [76, 77]) and viral (OAS1, OAS2, RNASEL, RIPK3, MD2, TLR4, GTF3A, IKBKE [78, 79, 80, 81, 82, 83]) infections (all AR LOF; Table 6, subtable 1);

  • Autoimmune/autoinflammatory disorders: PMVK, SHARPIN, LSM11, RNU71 (AR LOF);ALPK1, ARF1 (AD LOF);OTULIN (two entries, both AD); RELA (DN); and STAT4, LYN (AD GOF) (84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94). Heterozygous LOF variants in RELA have been previously described as causing mucocutaneous inflammation and fever but are included as a new disease in this update as novel descriptions of DN mutations are associated with an inflammatory phenotype driven by TLR7 upregulation and enhanced secretion of interferons (Table 7, subtable 1). Specific c.61G>C variants in NLRP3 are noted to cause keratitis fugax hereditaria (95, 96);

  • Bone marrow failure: DCLRE1B, DUT, RAD50 (97, 98, 99) (all AR LOF; Table 9, subtable 1);

  • Phenocopies of IEI: a somatic variant in JAK1 (AD GOF) (100) and autoantibodies against IL-27 (68) (Table 10, subtable 1).

New entries for each table are shown in bold in the Tables below.

Phenocopies of known IEIs confirm critical pathways for immune function

Some of these novel genetic findings link common clinical phenotypes that converge on a shared pathway. Examples in this update include the following:

  • PRIM1 encodes the catalytic subunit of the DNA primase as part of the DNA polymerase complex that includes POLA1 and POLD, mutations in which are associated with immunodeficiency and distinct syndromic features. Biallelic mutations in PRIM1 cause primordial dwarfism characterized by growth retardation, microcephaly, and developmental delay with B-cell deficiency, but unlike patients with defects in POLA1 and POLD have normal T-cell numbers with conserved proliferation (28).

  • GINS4 is a component of the DNA replication machinery of mammalian cells and forms part of multimeric/multiprotein “replisome” complexes (101). Biallelic mutations in GINS4 result in a clinical phenocopy of AR deficiency of MCM10, MCM4, or GINS1 genes (34, 102, 103) that encode key proteins involved in DNA replication (101).

  • Description of AR PMVK deficiency, which functions upstream of MVK, confirms the pathogenic effect of disturbed mevalonate metabolism, resulting in an autoinflammatory disease (87).

  • Recently described NUDCD3 deficiency builds on the crucial role of RAG-mediated recombination, with pathologic sequestration of RAG1 in the nucleoli in the absence of NUDCD3 (31).

IEIs define specific roles for known genes and reveal immune-specific functions of novel genes

The description of patients with IEIs and study of the pathogenic mechanism of IEIs can demonstrate nonredundant and redundant functions of a specific gene in human immunity, and reveal similarities and differences between functions of specific genes in mouse and human immunology. Examples are as follows:

  • NUDCD3 was mostly known as a chaperone protein, with only hints at a potential role in the immune system through interactome studies. We have now learned that it plays a crucial role in optimal localization of RAG1 necessary for recombination of T-cell and B-cell antigen receptors (31).

  • Studies in mice have established that FLT3L functions as a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) (104, 105). The identification of three patients with AR FLT3L deficiency confirmed that FLT3L is also required for B-cell and DC development in humans. However, unlike mice, human FLT3L is required for the development of monocytes but not NK cells (41).

  • Study of patients with PTCRA variants taught us that, unexpectedly, the majority have remained healthy at ages 2–65 years, whereas others had severe infection, lymphoproliferation, or autoimmunity, developing during adolescence or adulthood. Further investigation of individuals with hypomorphic PTCRA variants showed that memory αβ T cells can develop in the absence of human pre-TCRα and that human pre-TCRα is largely redundant for αβ T-cell development. However, complete or partial deficiency can lead to late-onset clinical manifestations, with incomplete penetrance (40).

  • PSMB10 was previously described as an AR disease gene for the autoinflammatory disorders PRAAS5, but specific, sporadic heterozygous variants in the same gene are clearly associated rather with a SCID/Omenn phenotype. The distinct behavior of such variants is not yet understood in terms of pathomechanism (32).

Recently identified IEIs have also revealed critical roles for genes in new disease contexts. For instance, our previous update highlighted the role of the type I IFN pathway in host defense against SARS-CoV-2 with the identification of germline defects in this pathway or autoantibodies against type I IFNs associated with severe COVID-19 (12). Subsequent studies related to the COVID-19 pandemic have included children presenting with multisystemic inflammatory syndrome (MIS-C) after SARS-CoV-2 infection and uncovered AR deficiencies of OAS1, OAS2, or RNASEL in around 1% of patients with this severe inflammatory complication. These gene products function in the same signaling pathway to suppress inflammation after double-stranded RNA detection. Thus, AR OAS1, OAS2, and RNASEL deficiencies result in uncontrolled inflammatory cytokine production that can underlie inflammation in some patients (78).

The role of autoantibodies in susceptibility to infections is a growing field. The identification of neutralizing autoantibodies against different cytokines has explained some aspects of the complex phenotypes of immune dysregulation in previously described IEIs, such as those affecting the alternative NF-κB pathway (106). In this update, we include autoantibodies directed against IL-27 underlying EBV infections (68), which phenocopy AR variants in IL27RA encoding one component of the IL-27R complex.

Somatic mutations as a phenocopy of IEI

Advances in sequencing techniques and analysis have enabled the identification of somatic variants as a cause of human immune diseases. Since IEIs have been defined as being caused by monogenic germline mutations, somatic mutations associated with disease are classified in Table 10 along with the phenocopies of IEI. Several somatic disorders have no germline disease equivalent. This is the case for VEXAS (an acronym for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome due to somatic mutation in UBA1 causing X-linked typically adult-onset immune dysregulation (107). In addition, there are diseases caused by either germline or somatic mutations including autoimmune lymphoproliferative syndrome due to FAS-FASL or RALD for which somatic mutations represent an important proportion of affected patients. All these disorders are included as phenocopies in Table 10. In this update, for several previously described AD autoinflammatory disorders, somatic mutations have been found to underlie a phenotype closely resembling that of germline variants affecting the same gene. Such is the case for somatic mutations in NLRP3, NOD2, TNFRSF1A, TNFAIP3, NLRC4, and MEFV (108, 109, 110, 111, 112, 113, 114) (indicated by ** in Tables 4 and 7). This growing list of immune disorders caused by somatic mutations underscores the need to consider variants detected at low allelic frequencies as possibly disease-causing, stressing the need for clinical laboratories to find ways to report these occurrences in addition to germline variants. We foresee that this list of somatic disorders resembling their IEI counterparts will increase with further advances in genetic sequencing and analysis techniques (115). In consideration of this, and to avoid redundancy, this committee has decided to denote such disorders throughout the manuscript to alert to the possibility of mosaicism as opposed to including them in Table 10 as different disorders.

Autoinflammation and immune dysregulation are at the forefront of novel discoveries blurring the borders between immunodeficiencies and rheumatology

Among the newly described genes, almost half (43%, 29/67) are either in the autoinflammatory or immune dysregulation tables. Autoimmune diseases affect around 10% of the population worldwide (116). These diseases have a complex etiology, where genetic and environmental factors interact, leading to a loss of tolerance against self-antigens, subsequent inflammation, and end-organ damage. B-cell dysregulation strongly contributes to the pathogenesis of several autoimmune diseases including SLE. The identification of new causes of monogenic lupus furthers our knowledge on how B cells are dysregulated and sheds light on new therapeutic targets. In this update, two novel gene defects are associated with monogenic lupus, namely, GOF variants in TLR7 (117) or UNC93B1 (23, 24). Remarkably, UNC93B1 is upstream of TLR7 and UNC93B1 GOF results in TLR7 hyperactivation, while TLR7 GOF variants result in aberrant survival of activated B cells. In addition, mutations in ERN1 (encoding IRE1α) disrupt XBP1 splicing and are associated with autoimmunity including SLE in one family member (66). In this update, we also include LACC1 as a monogenic cause of arthritis (64). Similar to COPA syndrome (118), monogenic arthritis due to biallelic LOF LACC1 variants is indistinguishable from polygenic arthritis. Thus, the identification of monogenic causes of arthritis may contribute to understanding pathophysiology and uncover new possibilities for precision medicine in rheumatology. As evidenced by the growing list of monogenic autoimmune disorders, the field of IEIs has become increasingly intertwined with rheumatology, underscoring the need to consider genetic analysis of patients with rheumatologic disease especially with, but not solely, onset in childhood. It is also important to note that the phenotypes of IEIs in general and specifically IEIs associated with autoimmunity and autoinflammation are increasingly overlapping.

Conclusions

In this update, the IUIS Expert Committee on IEI reports on 67 novel IEIs. These new gene defects bring the total number of IEIs to 559 (including four chromosomal deletion syndromes) resulting from variants in 508 genes (Fig. 1, A and B). The goals of the IUIS Expert Committee on IEI are to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of clinical immunology. The continuous increase in novel IEIs highlights the power of next-generation sequencing technologies with increased read depth also allowing for the detection of somatic mutations. Thorough and rigorous validation of candidate pathogenic variants enables us to (1) identify novel gene defects underlying human disease, (2) unveil mechanisms of disease pathogenesis, (3) define nonredundant functions of key genes in human immune cell development, host defense, and immune regulation, (4) expand the immunological and clinical phenotypes of IEIs, and (5) allow for future development of pathway- or gene-specific therapies. Collectively, the contributions of the researchers and scientists who discover novel IEIs will not only aid in diagnosing additional patients but also add to our fundamental knowledge of human immunology, as eloquently described in the inaugural Editorial for this journal by J.-L. Casanova (126).

Ethics approval

This work is a summary of recently reported genetic variants that represent novel IEIs. No human research studies were performed to produce this summary. Thus, no approvals by appropriate institutional review boards or human research ethics committees were required to undertake the preparation of this report.

Consent to Publish

The authors consent to publish the content of this summary. However, as noted above, as this is a summary of recently reported genetic variants that represent novel IEIs, we did not require consent to publish from participants.

The members of the Inborn Errors of Immunity Committee would like to thank the International Union of Immunological Societies.

This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. S.G. Tangye is supported by an Investigator Grant (Level 3) awarded by the National Health and Medical Research Council of Australia. I. Meyts is a senior clinical investigator of FWO Vlaanderen (EBD-D8974-FKM) and also supported by Jeffrey Model Foundation. M.C. Poli is supported by ANID Regular Investigator Grant FONDECYT 1221802 and Jeffrey Modell Foundation.

Author contributions: M.C. Poli: conceptualization, data curation, formal analysis, methodology, and writing—original draft, review, and editing. I. Aksentijevich: conceptualization, investigation, and writing—review and editing. A.A. Bousfiha: writing—original draft, review, and editing. C. Cunningham-Rundles: resources and writing—review and editing. S. Hambleto: investigation and writing—review and editing. C. Klein: conceptualization, formal analysis, investigation, validation, and writing—review and editing. T. Morio: conceptualization, data curation, and validation. C. Picard: visualization and writing—original draft, review, and editing. A. Puel: writing—review and editing. N. Rezaei: conceptualization, data curation, investigation, methodology, supervision, validation, and writing—original draft, review, and editing. M.R.J. Seppänen: data curation, formal analysis, resources, validation, and writing—review and editing. R. Somech: data curation, formal analysis, investigation, supervision, and validation. H.C. Su: writing—review and editing. K.E. Sullivan: conceptualization, formal analysis, and writing—review and editing. T.R. Torgerson: data curation, investigation, and writing—review and editing. I. Meyts: conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation, visualization, and writing—original draft, review, and editing. S.G. Tangye: conceptualization, data curation, investigation, project administration, supervision, and writing—original draft, review, and editing.

1.
Zhang
,
Q.
,
P.
Frange
,
S.
Blanche
, and
J.L.
Casanova
.
2017
.
Pathogenesis of infections in HIV-infected individuals: Insights from primary immunodeficiencies
.
Curr. Opin. Immunol.
48
:
122
–
133
.
https://doi.org/10.1016/j.coi.2017.09.002
Google Scholar
Crossref
Search ADS
PubMed
 
2.
Rider
,
N.L.
,
A.
Truxton
,
T.
Ohrt
,
I.
Margolin-Katz
,
M.
Horan
,
H.
Shin
,
R.
Davila
,
V.
Tenembaum
,
J.
Quinn
,
V.
Modell
, et al.
2024
.
Validating inborn error of immunity prevalence and risk with nationally representative electronic health record data
.
J. Allergy Clin. Immunol.
153
:
1704
–
1710
.
https://doi.org/10.1016/j.jaci.2024.01.011
Google Scholar
Crossref
Search ADS
PubMed
 
3.
Bousfiha
,
A.
,
L.
Jeddane
,
C.
Picard
,
W.
Al-Herz
,
F.
Ailal
,
T.
Chatila
,
C.
Cunningham-Rundles
,
A.
Etzioni
,
J.L.
Franco
,
S.M.
Holland
, et al.
2020
.
Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification
.
J. Clin. Immunol.
40
:
66
–
81
.
https://doi.org/10.1007/s10875-020-00758-x
Google Scholar
Crossref
Search ADS
PubMed
 
4.
Tangye
,
S.G.
,
W.
Al-Herz
,
A.
Bousfiha
,
T.
Chatila
,
C.
Cunningham-Rundles
,
A.
Etzioni
,
J.L.
Franco
,
S.M.
Holland
,
C.
Klein
,
T.
Morio
, et al.
2020
.
Human inborn errors of immunity: 2019 update on the classification from the international union of immunological societies expert committee
.
J. Clin. Immunol.
40
:
24
–
64
.
https://doi.org/10.1007/s10875-019-00737-x
Google Scholar
Crossref
Search ADS
PubMed
 
5.
Casanova
,
J.L.
, and
L.
Abel
.
2018
.
Human genetics of infectious diseases: Unique insights into immunological redundancy
.
Semin. Immunol.
36
:
1
–
12
.
https://doi.org/10.1016/j.smim.2017.12.008
Google Scholar
Crossref
Search ADS
PubMed
 
6.
Fischer
,
A.
, and
A.
Rausell
.
2018
.
What do primary immunodeficiencies tell us about the essentiality/redundancy of immune responses?
Semin. Immunol.
36
:
13
–
16
.
https://doi.org/10.1016/j.smim.2017.12.001
Google Scholar
Crossref
Search ADS
PubMed
 
7.
Good
,
R.A.
1968
.
Experiments of nature in immunobiology
.
N. Engl. J. Med.
279
:
1344
–
1345
.
https://doi.org/10.1056/NEJM196812122792411
Google Scholar
Crossref
Search ADS
PubMed
 
8.
Picard
,
C.
, and
A.
Fischer
.
2014
.
Contribution of high-throughput DNA sequencing to the study of primary immunodeficiencies
.
Eur. J. Immunol.
44
:
2854
–
2861
.
https://doi.org/10.1002/eji.201444669
Google Scholar
Crossref
Search ADS
PubMed
 
9.
Leiding
,
J.W.
, and
L.R.
Forbes
.
2019
.
Mechanism-based precision therapy for the treatment of primary immunodeficiency and primary immunodysregulatory diseases
.
J. Allergy Clin. Immunol. Pract.
7
:
761
–
773
.
https://doi.org/10.1016/j.jaip.2018.12.017
Google Scholar
Crossref
Search ADS
PubMed
 
10.
Ma
,
C.S.
, and
S.G.
Tangye
.
2019
.
Flow cytometric-based analysis of defects in lymphocyte differentiation and function due to inborn errors of immunity
.
Front. Immunol.
10
:
2108
.
https://doi.org/10.3389/fimmu.2019.02108
Google Scholar
Crossref
Search ADS
PubMed
 
11.
Casanova
,
J.L.
,
M.E.
Conley
,
S.J.
Seligman
,
L.
Abel
, and
L.D.
Notarangelo
.
2014
.
Guidelines for genetic studies in single patients: Lessons from primary immunodeficiencies
.
J. Exp. Med.
211
:
2137
–
2149
.
https://doi.org/10.1084/jem.20140520
Google Scholar
Crossref
Search ADS
PubMed
 
12.
Tangye
,
S.G.
,
W.
Al-Herz
,
A.
Bousfiha
,
C.
Cunningham-Rundles
,
J.L.
Franco
,
S.M.
Holland
,
C.
Klein
,
T.
Morio
,
E.
Oksenhendler
,
C.
Picard
, et al.
2022
.
Human inborn errors of immunity: 2022 update on the classification from the international union of immunological Societies expert committee
.
J. Clin. Immunol.
42
:
1473
–
1507
.
https://doi.org/10.1007/s10875-022-01289-3
Google Scholar
Crossref
Search ADS
PubMed
 
13.
Frémond
,
M.L.
, and
N.
Nathan
.
2021
.
COPA syndrome, 5 years after: Where are we?
Joint Bone Spine
.
88
:
105070
.
https://doi.org/10.1016/j.jbspin.2020.09.002
Google Scholar
Crossref
Search ADS
PubMed
 
14.
Delafontaine
,
S.
,
A.
Iannuzzo
,
T.M.
Bigley
,
B.
Mylemans
,
R.
Rana
,
P.
Baatsen
,
M.C.
Poli
,
D.
Rymen
,
K.
Jansen
,
D.
Mekahli
, et al.
2024
.
Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome
.
J. Clin. Invest.
134
:e163604.
https://doi.org/10.1172/JCI163604
Google Scholar
 
15.
Stewart
,
O.
,
C.
Gruber
,
H.E.
Randolph
,
R.
Patel
,
M.
Ramba
,
E.
Calzoni
,
L.H.
Huang
,
J.
Levy
,
S.
Buta
,
A.
Lee
, et al.
2025
.
Monoallelic expression can govern penetrance of inborn errors of immunity
.
Nature
.
637
:
1186
–
1197
.
https://doi.org/10.1038/s41586-024-08346-4
Google Scholar
Crossref
Search ADS
PubMed
 
16.
Bucciol
,
G.
,
L.
Moens
,
A.
Corveleyn
,
A.
Dreesman
, and
I.
Meyts
.
2022
.
A novel kindred with MyD88 deficiency
.
J. Clin. Immunol.
42
:
885
–
888
.
https://doi.org/10.1007/s10875-022-01240-6
Google Scholar
Crossref
Search ADS
PubMed
 
17.
Csomos
,
K.
,
B.
Ujhazi
,
P.
Blazso
,
J.L.
Herrera
,
C.M.
Tipton
,
T.
Kawai
,
S.
Gordon
,
M.
Ellison
,
K.
Wu
,
M.
Stowell
, et al.
2022
.
Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells
.
Nat. Immunol.
23
:
1256
–
1272
.
https://doi.org/10.1038/s41590-022-01271-6
Google Scholar
Crossref
Search ADS
PubMed
 
18.
Haque
,
N.
,
T.
Kawai
,
B.D.
Ratnasinghe
,
J.B.
Wagenknecht
,
R.
Urrutia
,
L.D.
Notarangelo
, and
M.T.
Zimmermann
.
2023
.
RAG genomic variation causes autoimmune diseases through specific structure-based mechanisms of enzyme dysregulation
.
iScience
.
26
:
108040
.
https://doi.org/10.1016/j.isci.2023.108040
Google Scholar
Crossref
Search ADS
PubMed
 
19.
Bucciol
,
G.
,
S.
Delafontaine
,
I.
Meyts
, and
C.
Poli
.
2024
.
Inborn errors of immunity: A field without frontiers
.
Immunol. Rev.
322
:
15
–
27
.
https://doi.org/10.1111/imr.13297
Google Scholar
Crossref
Search ADS
PubMed
 
20.
Fornes
,
O.
,
A.
Jia
,
H.S.
Kuehn
,
Q.
Min
,
U.
Pannicke
,
N.
Schleussner
,
R.
Thouenon
,
Z.
Yu
,
M.
de Los Angeles Astbury
,
C.M.
Biggs
, et al.
2023
.
A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency
.
Sci. Immunol.
8
:eade7953.
https://doi.org/10.1126/sciimmunol.ade7953
Google Scholar
 
21.
Guerin
A.
,
G.
Kerner
,
N.
Marr
,
J.G.
Markle
,
F.
Fenollar
,
N.
Wong
,
S.
Boughorbel
,
D.T.
Avery
,
C.S.
Ma
,
S.
Bougarn
, et al.
2018
.
IRF4 haploinsufficiency in a family with Whipple’s disease
.
Elife
.
7
:e32340.
https://doi.org/10.7554/eLife.32340
Google Scholar
 
22.
Thouenon
,
R.
,
L.
Chentout
,
N.
Moreno-Corona
,
L.
Poggi
,
E.P.
Lombardi
,
B.
Hoareau
,
Y.
Schmitt
,
C.
Lagresle-Peyrou
,
J.
Bustamante
,
I.
André
, et al.
2023
.
A neomorphic mutation in the interferon activation domain of IRF4 causes a dominant primary immunodeficiency
.
J. Exp. Med.
220
:e20221292.
https://doi.org/10.1084/jem.20221292
Google Scholar
 
23.
Wolf
,
C.
,
E.L.
Lim
,
M.
Mokhtari
,
B.
Kind
,
A.
Odainic
,
E.
Lara-Villacanas
,
S.
Koss
,
S.
Mages
,
K.
Menzel
,
K.
Engel
, et al.
2024
.
UNC93B1 variants underlie TLR7-dependent autoimmunity
.
Sci. Immunol.
9
:eadi9769.
https://doi.org/10.1126/sciimmunol.adi9769
Google Scholar
 
24.
David
,
C.
,
C.A.
Arango-Franco
,
M.
Badonyi
,
J.
Fouchet
,
G.I.
Rice
,
B.
Didry-Barca
,
L.
Maisonneuve
,
L.
Seabra
,
R.
Kechiche
,
C.
Masson
, et al.
2024
.
Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus
.
J. Exp. Med.
221
:e20232066.
https://doi.org/10.1084/jem.20232066
Google Scholar
 
25.
Al-Azab
,
M.
,
E.
Idiiatullina
,
Z.
Liu
,
M.
Lin
,
K.
Hrovat-Schaale
,
H.
Xian
,
J.
Zhu
,
M.
Yang
,
B.
Lu
,
Z.
Zhao
, et al.
2024
.
Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus
.
Nat. Immunol.
25
:
969
–
980
.
https://doi.org/10.1038/s41590-024-01846-5
Google Scholar
Crossref
Search ADS
PubMed
 
26.
Kostel Bal
,
S.
,
S.
Giuliani
,
J.
Block
,
P.
Repiscak
,
C.
Hafemeister
,
T.
Shahin
,
N.
Kasap
,
B.
Ransmayr
,
Y.
Miao
,
C.
van de Wetering
, et al.
2023
.
Biallelic NFATC1 mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis
.
Blood
.
142
:
827
–
845
.
https://doi.org/10.1182/blood.2022018303
Google Scholar
Crossref
Search ADS
PubMed
 
27.
Parry
,
D.A.
,
L.
Tamayo-Orrego
,
P.
Carroll
,
J.A.
Marsh
,
P.
Greene
,
O.
Murina
,
C.
Uggenti
,
A.
Leitch
,
R.
Káposzta
,
G.
Merő
, et al.
2020
.
PRIM1 deficiency causes a distinctive primordial dwarfism syndrome
.
Genes Dev.
34
:
1520
–
1533
.
https://doi.org/10.1101/gad.340190.120
Google Scholar
Crossref
Search ADS
PubMed
 
28.
Toskov
,
V.
,
P.
Kaiser-Labusch
,
M.A.
Lee-Kirsch
,
PRIM1 study group
,
S.
Ehl
, and
O.
Wegehaupt
.
2024
.
Variable syndromic immunodeficiency in patients with biallelic PRIM1 mutations
.
J. Clin. Immunol.
44
:
129
.
https://doi.org/10.1007/s10875-024-01733-6
Google Scholar
Crossref
Search ADS
PubMed
 
29.
Ghosh
,
R.
,
M.
Bosticardo
,
S.
Singh
,
M.
Similuk
,
O.M.
Delmonte
,
F.
Pala
,
C.
Peng
,
C.
Jodarski
,
M.D.
Keller
,
I.K.
Chinn
, et al.
2022
.
FOXI3 haploinsufficiency contributes to low T-cell receptor excision circles and T-cell lymphopenia
.
J. Allergy Clin. Immunol.
150
:
1556
–
1562
.
https://doi.org/10.1016/j.jaci.2022.08.005
Google Scholar
Crossref
Search ADS
PubMed
 
30.
Riestra
,
M.R.
,
B.A.
Pillay
,
M.
Willemsen
,
V.
Kienapfel
,
L.
Ehlers
,
S.
Delafontaine
,
A.
Pinton
,
M.
Wouters
,
A.
Hombrouck
,
K.
Sauer
, et al.
2023
.
Human autosomal recessive DNA polymerase delta 3 deficiency presenting as Omenn syndrome
.
J. Clin. Immunol.
44
:
2
.
https://doi.org/10.1007/s10875-023-01627-z
Google Scholar
Crossref
Search ADS
PubMed
 
31.
Chen
,
R.
,
E.
Lukianova
,
I.S.
van der Loeff
,
J.S.
Spegarova
,
J.D.P.
Willet
,
K.D.
James
,
E.J.
Ryder
,
H.
Griffin
,
H.
Ijspeert
,
A.
Gajbhiye
, et al.
2024
. NUDCD3
deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome
.
Sci. Immunol.
9
:eade5705.
https://doi.org/10.1126/sciimmunol.ade5705
Google Scholar
 
32.
van der Made
,
C.I.
,
S.
Kersten
,
O.
Chorin
,
K.R.
Engelhardt
,
G.
Ramakrishnan
,
H.
Griffin
,
I.
Schim van der Loeff
,
H.
Venselaar
,
A.R.
Rothschild
,
M.
Segev
, et al.
2024
.
Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome
.
Am. J. Hum. Genet.
111
:
791
–
804
.
https://doi.org/10.1016/j.ajhg.2024.02.013
Google Scholar
Crossref
Search ADS
PubMed
 
33.
Mohajeri
,
A.
,
M.
Vaseghi-Shanjani
,
J.A.
Rosenfeld
,
G.X.
Yang
,
H.
Lu
,
M.
Sharma
,
S.
Lin
,
A.
Salman
,
M.
Waqas
,
M.
Sababi Azamian
, et al.
2023
.
Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay
.
J. Med. Genet.
60
:
1092
–
1104
.
https://doi.org/10.1136/jmg-2022-109127
Google Scholar
Crossref
Search ADS
PubMed
 
34.
Conte
,
M.I.
,
M.C.
Poli
,
A.
Taglialatela
,
G.
Leuzzi
,
I.K.
Chinn
,
S.A.
Salinas
,
E.
Rey-Jurado
,
N.
Olivares
,
L.
Veramendi-Espinoza
,
A.
Ciccia
, et al.
2022
.
Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia
.
JCI Insight
.
7
:e154948.
https://doi.org/10.1172/jci.insight.154948
Google Scholar
 
35.
Sharma
,
M.
,
D.
Leung
,
M.
Momenilandi
,
L.C.W.
Jones
,
L.
Pacillo
,
A.E.
James
,
J.R.
Murrell
,
S.
Delafontaine
,
J.
Maimaris
,
M.
Vaseghi-Shanjani
, et al.
2023
.
Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease
.
J. Exp. Med.
220
:e20221755.
https://doi.org/10.1084/jem.20221755
Google Scholar
 
36.
Baris
,
S.
,
M.
Benamar
,
Q.
Chen
,
M.C.
Catak
,
M.
Martínez-Blanco
,
M.
Wang
,
J.
Fong
,
M.J.
Massaad
,
A.P.
Sefer
,
A.
Kara
, et al.
2023
.
Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6
.
J. Allergy Clin. Immunol.
152
:
182
–
194.e7
.
https://doi.org/10.1016/j.jaci.2023.01.023
Google Scholar
Crossref
Search ADS
PubMed
 
37.
Gök
,
V.
,
Ş.
Erdem
,
Y.
Haliloğlu
,
A.
Bişgin
,
S.
Belkaya
,
K.E.
Başaran
,
M.F.
Canatan
,
A.
Özcan
,
E.
Yılmaz
,
C.
Acıpayam
, et al.
2023
.
Immunodeficiency associated with a novel functionally defective variant of SLC19A1 benefits from folinic acid treatment
.
Genes Immun.
24
:
12
–
20
.
https://doi.org/10.1038/s41435-022-00191-7
Google Scholar
Crossref
Search ADS
PubMed
 
38.
Saba
,
J.D.
,
N.
Keller
,
J.Y.
Wang
,
F.
Tang
,
A.
Slavin
, and
Y.
Shen
.
2021
.
Genotype/phenotype interactions and first steps toward targeted therapy for sphingosine phosphate lyase insufficiency syndrome
.
Cell Biochem. Biophys.
79
:
547
–
559
.
https://doi.org/10.1007/s12013-021-01013-9
Google Scholar
Crossref
Search ADS
PubMed
 
39.
Tran
,
P.
,
M.
Jamee
,
Z.
Pournasiri
,
Z.
Chavoshzadeh
, and
K.E.
Sullivan
.
2023
.
SGPL1 deficiency: Nephrotic syndrome with lymphopenia
.
J. Clin. Immunol.
43
:
72
–
75
.
https://doi.org/10.1007/s10875-022-01348-9
Google Scholar
Crossref
Search ADS
PubMed
 
40.
Materna
,
M.
,
O.M.
Delmonte
,
M.
Bosticardo
,
M.
Momenilandi
,
P.E.
Conrey
,
B.
Charmeteau-De Muylder
,
C.
Bravetti
,
R.
Bellworthy
,
A.
Cederholm
,
F.
Staels
, et al.
2024
.
The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants
.
Science
.
383
:eadh4059.
https://doi.org/10.1126/science.adh4059
Google Scholar
 
41.
Momenilandi
,
M.
,
R.
Lévy
,
S.
Sobrino
,
J.
Li
,
C.
Lagresle-Peyrou
,
H.
Esmaeilzadeh
,
A.
Fayand
,
C.
Le Floc’h
,
A.
Guérin
,
E.
Della Mina
, et al.
2024
.
FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice
.
Cell
.
187
:
2817
–
2837.e31
.
https://doi.org/10.1016/j.cell.2024.04.009
Google Scholar
Crossref
Search ADS
PubMed
 
42.
Neumann
,
J.
,
E.
Van Nieuwenhove
,
L.E.
Terry
,
F.
Staels
,
T.R.
Knebel
,
K.
Welkenhuyzen
,
K.
Ahmadzadeh
,
M.R.
Baker
,
M.
Gerbaux
,
M.
Willemsen
, et al.
2023
.
Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional IP3 receptor subtype 3 defects
.
Cell. Mol. Immunol.
20
:
11
–
25
.
https://doi.org/10.1038/s41423-022-00928-4
Google Scholar
Crossref
Search ADS
PubMed
 
43.
De Somer
,
L.
,
C.
Wouters
,
M.A.
Morren
,
R.
De Vos
,
J.
Van Den Oord
,
K.
Devriendt
, and
I.
Meyts
.
2010
.
Granulomatous skin lesions complicating varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: Case report
.
Orphanet J. Rare Dis.
5
:
37
.
https://doi.org/10.1186/1750-1172-5-37
Google Scholar
Crossref
Search ADS
PubMed
 
44.
Broom
,
M.A.
,
L.L.
Wang
,
S.K.
Otta
,
A.P.
Knutsen
,
E.
Siegfried
,
J.R.
Batanian
,
M.E.
Kelly
, and
M.
Shah
.
2006
.
Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency
.
Clin. Genet.
69
:
337
–
343
.
https://doi.org/10.1111/j.1399-0004.2006.00592.x
Google Scholar
Crossref
Search ADS
PubMed
 
45.
Schepers
,
D.
,
G.
Tortora
,
H.
Morisaki
,
G.
MacCarrick
,
M.
Lindsay
,
D.
Liang
,
S.G.
Mehta
,
J.
Hague
,
J.
Verhagen
,
I.
van de Laar
, et al.
2018
.
A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3
.
Hum. Mutat.
39
:
621
–
634
.
https://doi.org/10.1002/humu.23407
Google Scholar
Crossref
Search ADS
PubMed
 
46.
Chesneau
,
B.
,
T.
Edouard
,
Y.
Dulac
,
H.
Colineaux
,
M.
Langeois
,
N.
Hanna
,
C.
Boileau
,
P.
Arnaud
,
N.
Chassaing
,
S.
Julia
, et al.
2020
.
Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature
.
Mol. Genet. Genomic Med.
8
:e1132.
https://doi.org/10.1002/mgg3.1132
Google Scholar
 
47.
Gouda
,
P.
,
R.
Kay
,
M.
Habib
,
A.
Aziz
,
E.
Aziza
, and
R.
Welsh
.
2022
.
Clinical features and complications of Loeys-Dietz syndrome: A systematic review
.
Int. J. Cardiol.
362
:
158
–
167
.
https://doi.org/10.1016/j.ijcard.2022.05.065
Google Scholar
Crossref
Search ADS
PubMed
 
48.
Kaiser
,
F.M.P.
,
S.
Gruenbacher
,
M.R.
Oyaga
,
E.
Nio
,
M.
Jaritz
,
Q.
Sun
,
W.
van der Zwaag
,
E.
Kreidl
,
L.M.
Zopf
,
V.A.S.H.
Dalm
, et al.
2022
.
Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder
.
J. Exp. Med.
219
:e20220498.
https://doi.org/10.1084/jem.20220498
Google Scholar
 
49.
Saettini
,
F.
,
F.
Guerra
,
G.
Fazio
,
C.
Bugarin
,
H.J.
McMillan
,
A.
Ohtake
,
A.
Ardissone
,
M.
Itoh
,
S.
Giglio
,
G.
Cappuccio
, et al.
2023
.
Antibody deficiency in patients with biallelic KARS1 mutations
.
J. Clin. Immunol.
43
:
2115
–
2125
.
https://doi.org/10.1007/s10875-023-01584-7
Google Scholar
Crossref
Search ADS
PubMed
 
50.
Saettini
,
F.
,
F.
Guerra
,
M.
Mauri
,
C.G.
Salter
,
M.P.
Adam
,
D.
Adams
,
E.L.
Baple
,
E.
Barredo
,
S.
Bhatia
,
A.
Borkhardt
, et al.
2024
.
Biallelic PI4KA mutations disrupt B-cell metabolism and cause B-cell lymphopenia and hypogammaglobulinemia
.
J. Clin. Immunol.
45
:
15
.
https://doi.org/10.1007/s10875-024-01793-8
Google Scholar
Crossref
Search ADS
PubMed
 
51.
Johnson
,
M.B.
,
M.
Ogishi
,
C.
Domingo-Vila
,
E.
De Franco
,
M.N.
Wakeling
,
Z.
Imane
,
B.
Resnick
,
E.
Williams
,
R.P.
Galão
,
R.
Caswell
, et al.
2024
.
Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency
.
J. Exp. Med.
221
:e20231704.
https://doi.org/10.1084/jem.20231704
Google Scholar
 
52.
Mishra
,
H.
,
C.
Schlack-Leigers
,
E.L.
Lim
,
O.
Thieck
,
T.
Magg
,
J.
Raedler
,
C.
Wolf
,
C.
Klein
,
H.
Ewers
,
M.A.
Lee-Kirsch
, et al.
2024
.
Disrupted degradative sorting of TLR7 is associated with human lupus
.
Sci. Immunol.
9
:eadi9575.
https://doi.org/10.1126/sciimmunol.adi9575
Google Scholar
 
53.
Stremenova Spegarova
,
J.
,
P.
Sinnappurajar
,
D.
Al Julandani
,
R.
Navickas
,
H.
Griffin
,
M.
Ahuja
,
A.
Grainger
,
K.
Livingstone
,
G.I.
Rice
,
F.
Sutherland
, et al.
2024
.
A de novo TLR7 gain-of-function mutation causing severe monogenic lupus in an infant
.
J. Clin. Invest.
134
:e179193.
https://doi.org/10.1172/JCI179193
Google Scholar
 
54.
Rae
,
W.
,
J.M.
Sowerby
,
D.
Verhoeven
,
M.
Youssef
,
P.
Kotagiri
,
N.
Savinykh
,
E.L.
Coomber
,
A.
Boneparth
,
A.
Chan
,
C.
Gong
, et al.
2022
.
Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations
.
Sci. Immunol.
7
:eabn3800.
https://doi.org/10.1126/sciimmunol.abn3800
Google Scholar
 
55.
Li
,
X.
,
W.
Sun
,
M.
Huang
,
L.
Gong
,
X.
Zhang
,
L.
Zhong
,
V.
Calderon
,
Z.
Bian
,
Y.
He
,
W.K.
Suh
, et al.
2024
.
Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation
.
Immunity
.
57
:
1603
–
1617.e7
.
https://doi.org/10.1016/j.immuni.2024.04.023
Google Scholar
Crossref
Search ADS
PubMed
 
56.
Tao
,
P.
,
X.
Han
,
Q.
Wang
,
S.
Wang
,
J.
Zhang
,
L.
Liu
,
X.
Fan
,
C.
Liu
,
M.
Liu
,
L.
Guo
, et al.
2023
.
A gain-of-function variation in PLCG1 causes a new immune dysregulation disease
.
J. Allergy Clin. Immunol.
152
:
1292
–
1302
.
https://doi.org/10.1016/j.jaci.2023.06.020
Google Scholar
Crossref
Search ADS
PubMed
 
57.
Blombery
,
P.
,
V.
Pazhakh
,
A.S.
Albuquerque
,
J.
Maimaris
,
L.
Tu
,
B.
Briones Miranda
,
F.
Evans
,
E.R.
Thompson
,
B.
Carpenter
,
I.
Proctor
, et al.
2023
.
Biallelic deleterious germline SH2B3 variants cause a novel syndrome of myeloproliferation and multi-organ autoimmunity
.
EJHaem
.
4
:
463
–
469
.
https://doi.org/10.1002/jha2.698
Google Scholar
Crossref
Search ADS
PubMed
 
58.
Sindram
,
E.
,
A.
Caballero-Oteyza
,
N.
Kogata
,
S.
Chor Mei Huang
,
Z.
Alizadeh
,
L.
Gámez-Díaz
,
M.R.
Fazlollhi
,
X.
Peng
,
B.
Grimbacher
,
M.
Way
, and
M.
Proietti
.
2023
.
ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality
.
Dis. Model. Mech.
16
:
dmm050145
.
https://doi.org/10.1242/dmm.050145
Google Scholar
Crossref
Search ADS
PubMed
 
59.
Erman
,
B.
,
S.K.
Bal
,
Ç.
Aydoğmuş
,
G.Z.
Ersoy
, and
K.
Boztug
.
2024
.
A novel homozygous six base pair deletion found in the NFATC2 gene in a patient with EBV-associated lymphoproliferation
.
J. Clin. Immunol.
44
:
74
.
https://doi.org/10.1007/s10875-024-01675-z
Google Scholar
Crossref
Search ADS
PubMed
 
60.
Sharma
,
M.
,
M.P.
Fu
,
H.Y.
Lu
,
A.A.
Sharma
,
B.P.
Modi
,
C.
Michalski
,
S.
Lin
,
J.
Dalmann
,
A.
Salman
,
K.L.
Del Bel
, et al.
2022
.
Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy
.
Blood
.
140
:
1858
–
1874
.
https://doi.org/10.1182/blood.2022015674
Google Scholar
Crossref
Search ADS
PubMed
 
61.
Block
,
J.
,
C.
Rashkova
,
I.
Castanon
,
S.
Zoghi
,
J.
Platon
,
R.C.
Ardy
,
M.
Fujiwara
,
B.
Chaves
,
R.
Schoppmeyer
,
C.I.
van der Made
, et al.
2023
.
Systemic inflammation and normocytic anemia in DOCK11 deficiency
.
N. Engl. J. Med.
389
:
527
–
539
.
https://doi.org/10.1056/NEJMoa2210054
Google Scholar
Crossref
Search ADS
PubMed
 
62.
Boussard
,
C.
,
L.
Delage
,
T.
Gajardo
,
A.
Kauskot
,
M.
Batignes
,
N.
Goudin
,
M.C.
Stolzenberg
,
C.
Brunaud
,
P.
Panikulam
,
Q.
Riller
, et al.
2023
.
DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity
.
Blood
.
141
:
2713
–
2726
.
https://doi.org/10.1182/blood.2022018486
Google Scholar
Crossref
Search ADS
PubMed
 
63.
Kubo
,
S.
,
J.M.
Fritz
,
H.M.
Raquer-McKay
,
R.
Kataria
,
I.
Vujkovic-Cvijin
,
A.
Al-Shaibi
,
Y.
Yao
,
L.
Zheng
,
J.
Zou
,
A.D.
Waldman
, et al.
2022
.
Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease
.
Nat. Immunol.
23
:
75
–
85
.
https://doi.org/10.1038/s41590-021-01093-y
Google Scholar
Crossref
Search ADS
PubMed
 
64.
Omarjee
,
O.
,
A.L.
Mathieu
,
G.
Quiniou
,
M.
Moreews
,
M.
Ainouze
,
C.
Frachette
,
I.
Melki
,
C.
Dumaine
,
M.
Gerfaud-Valentin
,
A.
Duquesne
, et al.
2021
.
LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages
.
J. Exp. Med.
218
:e20201006.
https://doi.org/10.1084/jem.20201006
Google Scholar
 
65.
Wakil
,
S.M.
,
D.M.
Monies
,
M.
Abouelhoda
,
N.
Al-Tassan
,
H.
Al-Dusery
,
E.A.
Naim
,
B.
Al-Younes
,
J.
Shinwari
,
F.A.
Al-Mohanna
,
B.F.
Meyer
, and
S.
Al-Mayouf
.
2015
.
Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis
.
Arthritis Rheumatol.
67
:
288
–
295
.
https://doi.org/10.1002/art.38877
Google Scholar
Crossref
Search ADS
PubMed
 
66.
Reuschlé
,
Q.
,
L.
Van Heddegem
,
V.
Bosteels
,
M.
Moncan
,
S.
Depauw
,
N.
Wadier
,
S.
Maréchal
,
C.
De Nolf
,
V.
Delgado
,
Y.
Messai
, et al.
2024
.
Loss of function of XBP1 splicing activity of IRE1α favors B cell tolerance breakdown
.
J. Autoimmun.
142
:
103152
.
https://doi.org/10.1016/j.jaut.2023.103152
Google Scholar
Crossref
Search ADS
PubMed
 
67.
Delage
,
L.
,
F.
Carbone
,
Q.
Riller
,
J.L.
Zachayus
,
E.
Kerbellec
,
A.
Buzy
,
M.C.
Stolzenberg
,
M.
Luka
,
C.
de Cevins
,
G.
Kalouche
, et al.
2023
.
NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells
.
Nat. Commun.
14
:
3728
.
https://doi.org/10.1038/s41467-023-39295-7
Google Scholar
Crossref
Search ADS
PubMed
 
68.
Martin
,
E.
,
S.
Winter
,
C.
Garcin
,
K.
Tanita
,
A.
Hoshino
,
C.
Lenoir
,
B.
Fournier
,
M.
Migaud
,
D.
Boutboul
,
M.
Simonin
, et al.
2024
.
Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency
.
Nature
.
628
:
620
–
629
.
https://doi.org/10.1038/s41586-024-07213-6
Google Scholar
Crossref
Search ADS
PubMed
 
69.
Fournier
,
B.
,
A.
Hoshino
,
J.
Bruneau
,
C.
Bachelet
,
M.
Fusaro
,
R.
Klifa
,
R.
Lévy
,
C.
Lenoir
,
C.
Soudais
,
C.
Picard
, et al.
2022
.
Inherited TNFSF9 deficiency causes broad Epstein-Barr virus infection with EBV+ smooth muscle tumors
.
J. Exp. Med.
219
:e20211682.
https://doi.org/10.1084/jem.20211682
Google Scholar
 
70.
Harapas
,
C.R.
,
K.S.
Robinson
,
K.
Lay
,
J.
Wong
,
R.
Moreno Traspas
,
N.
Nabavizadeh
,
A.
Rass-Rothschild
,
B.
Boisson
,
S.B.
Drutman
,
P.
Laohamonthonkul
, et al.
2022
.
DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling
.
Sci. Immunol.
7
:eabi4611.
https://doi.org/10.1126/sciimmunol.abi4611
Google Scholar
 
71.
Yao
,
Y.
,
P.
Du Jiang
,
B.N.
Chao
,
D.
Cagdas
,
S.
Kubo
,
A.
Balasubramaniyam
,
Y.
Zhang
,
B.
Shadur
,
A.
NaserEddin
,
L.R.
Folio
, et al.
2022
.
GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans
.
J. Exp. Med.
219
:e20201405.
https://doi.org/10.1084/jem.20201405
Google Scholar
 
72.
Jeanpierre
,
M.
,
J.
Cognard
,
M.
Tusseau
,
Q.
Riller
,
L.C.
Bui
,
J.
Berthelet
,
A.
Laurent
,
E.
Crickx
,
M.
Parlato
,
M.C.
Stolzenberg
, et al.
2024
.
Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus
.
J. Exp. Med.
221
:e20232337.
https://doi.org/10.1084/jem.20232337
Google Scholar
 
73.
Willemsen
,
M.
,
A.
De Visscher
,
J.
Filtjens
,
I.
Meyts
,
P.
Matthys
,
S.
Humblet-Baron
, and
A.
Liston
.
2024
.
An immature NK cell compartment in functional DBF4 deficiency
.
J. Clin. Immunol.
44
:
146
.
https://doi.org/10.1007/s10875-024-01750-5
Google Scholar
Crossref
Search ADS
PubMed
 
74.
Linder
,
M.I.
,
Y.
Mizoguchi
,
S.
Hesse
,
G.
Csaba
,
M.
Tatematsu
,
M.
Łyszkiewicz
,
N.
Ziȩtara
,
T.
Jeske
,
M.
Hastreiter
,
M.
Rohlfs
, et al.
2023
.
Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes
.
Blood
.
141
:
645
–
658
.
https://doi.org/10.1182/blood.2022016783
Google Scholar
Crossref
Search ADS
PubMed
 
75.
Neehus
,
A.L.
,
B.
Carey
,
M.
Landekic
,
P.
Panikulam
,
G.
Deutsch
,
M.
Ogishi
,
C.A.
Arango-Franco
,
Q.
Philippot
,
M.
Modaresi
,
I.
Mohammadzadeh
, et al.
2024
.
Human inherited CCR2 deficiency underlies progressive polycystic lung disease
.
Cell
.
187
:
390
–
408.e23
.
https://doi.org/10.1016/j.cell.2023.11.036
Google Scholar
Crossref
Search ADS
PubMed
 
76.
Rosain
,
J.
,
A.L.
Neehus
,
J.
Manry
,
R.
Yang
,
J.
Le Pen
,
W.
Daher
,
Z.
Liu
,
Y.H.
Chan
,
N.
Tahuil
,
Ö.
Türel
, et al.
2023
.
Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria
.
Cell
.
186
:
621
–
645.e33
.
https://doi.org/10.1016/j.cell.2022.12.038
Google Scholar
Crossref
Search ADS
PubMed
 
77.
Bohlen
,
J.
,
Q.
Zhou
,
Q.
Philippot
,
M.
Ogishi
,
D.
Rinchai
,
T.
Nieminen
,
S.
Seyedpour
,
N.
Parvaneh
,
N.
Rezaei
,
N.
Yazdanpanah
, et al.
2023
.
Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria
.
Cell
.
186
:
5114
–
5134.e27
.
https://doi.org/10.1016/j.cell.2023.09.024
Google Scholar
Crossref
Search ADS
PubMed
 
78.
Lee
,
D.
,
J.
Le Pen
,
A.
Yatim
,
B.
Dong
,
Y.
Aquino
,
M.
Ogishi
,
R.
Pescarmona
,
E.
Talouarn
,
D.
Rinchai
,
P.
Zhang
, et al.
2023
.
Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children
.
Science
.
379
:eabo3627.
https://doi.org/10.1126/science.abo3627
Google Scholar
 
79.
Liu
,
Z.
,
E.J.
Garcia Reino
,
O.
Harschnitz
,
H.
Guo
,
Y.H.
Chan
,
N.V.
Khobrekar
,
M.L.
Hasek
,
K.
Dobbs
,
D.
Rinchai
,
M.
Materna
, et al.
2023
.
Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency
.
Sci. Immunol.
8
:eade2860.
https://doi.org/10.1126/sciimmunol.ade2860
Google Scholar
 
80.
Li
,
Y.
,
Z.
Yu
,
M.
Schenk
,
I.
Lagovsky
,
D.
Illig
,
C.
Walz
,
M.
Rohlfs
,
R.
Conca
,
A.M.
Muise
,
S.B.
Snapper
, et al.
2023
.
Human MD2 deficiency-an inborn error of immunity with pleiotropic features
.
J. Allergy Clin. Immunol.
151
:
791
–
796.e7
.
https://doi.org/10.1016/j.jaci.2022.09.033
Google Scholar
Crossref
Search ADS
PubMed
 
81.
Capitani
,
M.
,
A.A.
Al-Shaibi
,
S.
Pandey
,
L.
Gartner
,
H.
Taylor
,
S.Z.
Hubrack
,
N.
Agrebi
,
M.J.
Al-Mohannadi
,
S.
Al Kaabi
,
T.
Vogl
, et al.
2023
.
Biallelic TLR4 deficiency in humans
.
J. Allergy Clin. Immunol.
151
:
783
–
790.e5
.
https://doi.org/10.1016/j.jaci.2022.08.030
Google Scholar
Crossref
Search ADS
PubMed
 
82.
Naesens
,
L.
,
S.
Muppala
,
D.
Acharya
,
J.
Nemegeer
,
D.
Bogaert
,
J.H.
Lee
,
K.
Staes
,
V.
Debacker
,
P.
De Bleser
,
M.
De Bruyne
, et al.
2022
.
GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141
.
Sci. Immunol.
7
:eabq4531.
https://doi.org/10.1126/sciimmunol.abq4531
Google Scholar
 
83.
Reyahi
,
A.
,
M.
Studahl
,
M.K.
Skouboe
,
S.
Fruhwürth
,
R.
Narita
,
F.
Ren
,
M.
Bjerhem Viklund
,
M.B.
Iversen
,
M.
Christiansen
,
A.
Svensson
, et al.
2023
.
An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis
.
JCI Insight
.
8
:e173066.
https://doi.org/10.1172/jci.insight.173066
Google Scholar
 
84.
Uggenti
,
C.
,
A.
Lepelley
,
M.
Depp
,
A.P.
Badrock
,
M.P.
Rodero
,
M.T.
El-Daher
,
G.I.
Rice
,
S.
Dhir
,
A.P.
Wheeler
,
A.
Dhir
, et al.
2020
.
cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing
.
Nat. Genet.
52
:
1364
–
1372
.
https://doi.org/10.1038/s41588-020-00737-3
Google Scholar
Crossref
Search ADS
PubMed
 
85.
Naesens
,
L.
,
J.
Nemegeer
,
F.
Roelens
,
L.
Vallaeys
,
M.
Meuwissen
,
K.
Janssens
,
P.
Verloo
,
B.
Ogunjimi
,
D.
Hemelsoet
,
L.
Hoste
, et al.
2022
.
Mutations in RNU7-1 weaken secondary RNA structure, induce MCP-1 and CXCL10 in CSF, and result in Aicardi-Goutières syndrome with severe end-organ involvement
.
J. Clin. Immunol.
42
:
962
–
974
.
https://doi.org/10.1007/s10875-022-01209-5
Google Scholar
Crossref
Search ADS
PubMed
 
86.
Baghdassarian
,
H.
,
S.A.
Blackstone
,
O.S.
Clay
,
R.
Philips
,
B.
Matthiasardottir
,
M.
Nehrebecky
,
V.K.
Hua
,
R.
McVicar
,
Y.
Liu
,
S.M.
Tucker
, et al.
2023
.
Variant STAT4 and response to ruxolitinib in an autoinflammatory syndrome
.
N. Engl. J. Med.
388
:
2241
–
2252
.
https://doi.org/10.1056/NEJMoa2202318
Google Scholar
Crossref
Search ADS
PubMed
 
87.
Berner
,
J.
,
C.
van de Wetering
,
R.
Jimenez Heredia
,
C.
Rashkova
,
S.
Ferdinandusse
,
J.
Koster
,
J.G.
Weiss
,
A.
Frohne
,
S.
Giuliani
,
H.R.
Waterham
, et al.
2023
.
Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases
.
J. Allergy Clin. Immunol.
152
:
1025
–
1031.e2
.
https://doi.org/10.1016/j.jaci.2023.06.013
Google Scholar
Crossref
Search ADS
PubMed
 
88.
Kozycki
,
C.T.
,
S.
Kodati
,
L.
Huryn
,
H.
Wang
,
B.M.
Warner
,
P.
Jani
,
D.
Hammoud
,
M.S.
Abu-Asab
,
Y.
Jittayasothorn
,
M.J.
Mattapallil
, et al.
2022
.
Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: Functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome
.
Ann. Rheum. Dis.
81
:
1453
–
1464
.
https://doi.org/10.1136/annrheumdis-2022-222629
Google Scholar
Crossref
Search ADS
PubMed
 
89.
Louvrier
,
C.
,
E.
El Khouri
,
M.
Grall Lerosey
,
P.
Quartier
,
A.M.
Guerrot
,
B.
Bader Meunier
,
J.
Chican
,
M.
Mohammad
,
E.
Assrawi
,
A.
Daskalopoulou
, et al.
2023
.
De novo gain-of-function variations in LYN associated with an early-onset systemic autoinflammatory disorder
.
Arthritis Rheumatol.
75
:
468
–
474
.
https://doi.org/10.1002/art.42354
Google Scholar
Crossref
Search ADS
PubMed
 
90.
Oda
,
H.
,
K.
Manthiram
,
P.P.
Chavan
,
E.
Rieser
,
Ö.
Veli
,
Ö.
Kaya
,
C.
Rauch
,
S.
Nakabo
,
H.S.
Kuehn
,
M.
Swart
, et al.
2024
.
Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency
.
Nat. Immunol.
25
:
764
–
777
.
https://doi.org/10.1038/s41590-024-01817-w
Google Scholar
Crossref
Search ADS
PubMed
 
91.
Staels
,
F.
,
L.
Bücken
,
L.
De Vuyst
,
M.
Willemsen
,
E.
Van Nieuwenhove
,
M.
Gerbaux
,
J.
Neumann
,
V.
Malviya
,
L.
Van Meerbeeck
,
J.
Haughton
, et al.
2024
.
OTULIN haploinsufficiency predisposes to environmentally directed inflammation
.
Front. Immunol.
15
:
983686
.
https://doi.org/10.3389/fimmu.2024.983686
Google Scholar
Crossref
Search ADS
PubMed
 
92.
Spaan
,
A.N.
2024
.
OTULIN and Muller’s morphs
.
J. Exp. Med.
221
:e20240418.
https://doi.org/10.1084/jem.20240418
Google Scholar
 
93.
Moriya
,
K.
,
T.
Nakano
,
Y.
Honda
,
M.
Tsumura
,
M.
Ogishi
,
M.
Sonoda
,
M.
Nishitani-Isa
,
T.
Uchida
,
M.
Hbibi
,
Y.
Mizoguchi
, et al.
2023
.
Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity
.
J. Exp. Med.
220
:e20212276.
https://doi.org/10.1084/jem.20212276
Google Scholar
 
94.
Hirschenberger
,
M.
,
A.
Lepelley
,
U.
Rupp
,
S.
Klute
,
V.
Hunszinger
,
L.
Koepke
,
V.
Merold
,
B.
Didry-Barca
,
F.
Wondany
,
T.
Bergner
, et al.
2023
.
ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
.
Nat. Commun.
14
:
6770
.
https://doi.org/10.1038/s41467-023-42150-4
Google Scholar
Crossref
Search ADS
PubMed
 
95.
Immonen
,
A.T.
,
S.
Kawan
,
M.
Vesaluoma
,
J.M.
Heiskanen
,
C.
Taipale
,
M.
Koskinen
,
A.
Majander
,
T.T.
Kivelä
, and
J.A.
Turunen
.
2022
.
Clinical spectrum and geographic distribution of keratitis fugax hereditaria caused by the pathogenic variant c.61G>C in NLRP3
.
Am. J. Ophthalmol.
236
:
309
–
318
.
https://doi.org/10.1016/j.ajo.2021.10.025
Google Scholar
Crossref
Search ADS
PubMed
 
96.
Kawan
,
S.
,
M.P.
Backlund
,
A.T.
Immonen
,
T.T.
Kivelä
, and
J.A.
Turunen
.
2024
.
Functional consequences of pathogenic variant c.61G>C in the inflammasome gene NLRP3 underlying keratitis fugax hereditaria
.
Br. J. Ophthalmol.
108
:
323
–
328
.
https://doi.org/10.1136/bjo-2022-321825
Google Scholar
Crossref
Search ADS
PubMed
 
97.
Kermasson
,
L.
,
D.
Churikov
,
A.
Awad
,
R.
Smoom
,
E.
Lainey
,
F.
Touzot
,
S.
Audebert-Bellanger
,
S.
Haro
,
L.
Roger
,
E.
Costa
, et al.
2022
.
Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects
.
Blood
.
139
:
2427
–
2440
.
https://doi.org/10.1182/blood.2021010791
Google Scholar
Crossref
Search ADS
PubMed
 
98.
Dos Santos
,
R.S.
,
M.
Daures
,
A.
Philippi
,
S.
Romero
,
L.
Marselli
,
P.
Marchetti
,
V.
Senée
,
D.
Bacq
,
C.
Besse
,
B.
Baz
, et al.
2017
.
dUTPase (DUT) is mutated in a novel monogenic syndrome with diabetes and bone marrow failure
.
Diabetes
.
66
:
1086
–
1096
.
https://doi.org/10.2337/db16-0839
Google Scholar
Crossref
Search ADS
PubMed
 
99.
Takagi
,
M.
,
A.
Hoshino
,
K.
Bousset
,
J.
Röddecke
,
H.L.
Martin
,
I.
Folcut
,
D.
Tomomasa
,
X.
Yang
,
J.
Kobayashi
,
N.
Sakata
, et al.
2023
.
Bone marrow failure and immunodeficiency associated with human RAD50 variants
.
J. Clin. Immunol.
43
:
2136
–
2145
.
https://doi.org/10.1007/s10875-023-01591-8
Google Scholar
Crossref
Search ADS
PubMed
 
100.
Gruber
,
C.N.
,
J.J.A.
Calis
,
S.
Buta
,
G.
Evrony
,
J.C.
Martin
,
S.A.
Uhl
,
R.
Caron
,
L.
Jarchin
,
D.
Dunkin
,
R.
Phelps
, et al.
2020
.
Complex autoinflammatory syndrome unveils fundamental principles of JAK1 kinase transcriptional and biochemical function
.
Immunity
.
53
:
672
–
684.e11
.
https://doi.org/10.1016/j.immuni.2020.07.006
Google Scholar
Crossref
Search ADS
PubMed
 
101.
Bellelli
,
R.
, and
S.J.
Boulton
.
2021
.
Spotlight on the replisome: Aetiology of DNA replication-associated genetic diseases
.
Trends Genet.
37
:
317
–
336
.
https://doi.org/10.1016/j.tig.2020.09.008
Google Scholar
Crossref
Search ADS
PubMed
 
102.
Mace
,
E.M.
,
S.
Paust
,
M.I.
Conte
,
R.M.
Baxley
,
M.M.
Schmit
,
S.L.
Patil
,
N.C.
Guilz
,
M.
Mukherjee
,
A.E.
Pezzi
,
J.
Chmielowiec
, et al.
2020
.
Human NK cell deficiency as a result of biallelic mutations in MCM10
.
J. Clin. Invest.
130
:
5272
–
5286
.
https://doi.org/10.1172/JCI134966
Google Scholar
Crossref
Search ADS
PubMed
 
103.
Baxley
,
R.M.
,
W.
Leung
,
M.M.
Schmit
,
J.P.
Matson
,
L.
Yin
,
M.K.
Oram
,
L.
Wang
,
J.
Taylor
,
J.
Hedberg
,
C.B.
Rogers
, et al.
2021
.
Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening
.
Nat. Commun.
12
:
1626
.
https://doi.org/10.1038/s41467-021-21878-x
Google Scholar
Crossref
Search ADS
PubMed
 
104.
Régnier
,
P.
,
M.
Vetillard
,
A.
Bansard
,
E.
Pierre
,
X.
Li
,
N.
Cagnard
,
E.L.
Gautier
,
P.
Guermonprez
,
B.
Manoury
,
K.
Podsypanina
, and
G.
Darrasse-Jèze
.
2023
.
FLT3L-dependent dendritic cells control tumor immunity by modulating Treg and NK cell homeostasis
.
Cell Rep. Med.
4
:
101256
.
https://doi.org/10.1016/j.xcrm.2023.101256
Google Scholar
Crossref
Search ADS
PubMed
 
105.
Sikder
,
M.A.A.
,
R.B.
Rashid
,
T.
Ahmed
,
I.
Sebina
,
D.R.
Howard
,
M.A.
Ullah
,
M.M.
Rahman
,
J.P.
Lynch
,
B.
Curren
,
R.B.
Werder
, et al.
2023
.
Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection
.
Immunity
.
56
:
1098
–
1114.e10
.
https://doi.org/10.1016/j.immuni.2023.03.002
Google Scholar
Crossref
Search ADS
PubMed
 
106.
Le Voyer
,
T.
,
A.V.
Parent
,
X.
Liu
,
A.
Cederholm
,
A.
Gervais
,
J.
Rosain
,
T.
Nguyen
,
M.
Perez Lorenzo
,
E.
Rackaityte
,
D.
Rinchai
, et al.
2023
.
Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
.
Nature
.
623
:
803
–
813
.
https://doi.org/10.1038/s41586-023-06717-x
Google Scholar
Crossref
Search ADS
PubMed
 
107.
Beck
,
D.B.
,
M.A.
Ferrada
,
K.A.
Sikora
,
A.K.
Ombrello
,
J.C.
Collins
,
W.
Pei
,
N.
Balanda
,
D.L.
Ross
,
D.
Ospina Cardona
,
Z.
Wu
, et al.
2020
.
Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease
.
N. Engl. J. Med.
383
:
2628
–
2638
.
https://doi.org/10.1056/NEJMoa2026834
Google Scholar
Crossref
Search ADS
PubMed
 
108.
Lin
,
Y.
,
C.
Zeng
,
X.
Chen
,
T.
Li
,
H.
Liu
,
H.
Liu
,
H.
Hu
, and
L.
Liu
.
2020
.
Chinese family with Blau syndrome: Mutated NOD2 allele transmitted from the father with de novo somatic and germ line mosaicism
.
J. Dermatol.
47
:e395.
https://doi.org/10.1111/1346-8138.15563
Google Scholar
 
109.
Assrawi
,
E.
,
C.
Louvrier
,
E.
El Khouri
,
J.
Delaleu
,
B.
Copin
,
F.
Dastot-Le Moal
,
W.
Piterboth
,
M.
Legendre
,
S.A.
Karabina
,
G.
Grateau
, et al.
2022
.
Mosaic variants in TNFRSF1A: An emerging cause of tumour necrosis factor receptor-associated periodic syndrome
.
Rheumatology (Oxford)
.
62
:
473
–
479
.
https://doi.org/10.1093/rheumatology/keac274
Google Scholar
Crossref
Search ADS
PubMed
 
110.
Kontzias
,
A.
,
S.K.
Zarabi
,
C.
Calabrese
,
Y.
Wang
,
L.
Judis
,
Q.
Yao
, and
Y.W.
Cheng
.
2019
.
Somatic mosaicism in adult-onset TNF receptor-associated periodic syndrome (TRAPS)
.
Mol. Genet. Genomic Med.
7
:e791.
https://doi.org/10.1002/mgg3.791
Google Scholar
 
111.
Ionescu
,
D.
,
A.
Peñín-Franch
,
A.
Mensa-Vilaró
,
P.
Castillo
,
L.
Hurtado-Navarro
,
C.
Molina-López
,
S.
Romero-Chala
,
S.
Plaza
,
V.
Fabregat
,
S.
Buján
, et al.
2022
.
First description of late-onset autoinflammatory disease due to somatic NLRC4 mosaicism
.
Arthritis Rheumatol.
74
:
692
–
699
.
https://doi.org/10.1002/art.41999
Google Scholar
Crossref
Search ADS
PubMed
 
112.
Terré
,
A.
,
F.
Magnotti
,
J.M.
Piot
,
G.
Boursier
, and
S.
Georgin-Lavialle
.
2024
.
Pyrin-associated autoinflammatory disease with p.Thr577Ala MEFV somatic mutation
.
Eur. J. Intern. Med.
120
:
139
–
141
.
https://doi.org/10.1016/j.ejim.2023.11.014
Google Scholar
Crossref
Search ADS
PubMed
 
113.
Parentelli
A.S.
,
G.
Boursier
,
L.
Cuisset
, and
S.
Georgin-Lavialle
.
2024
.
[Genetic mosaicism in systemic auto-inflammatory diseases: A review of the literature]
.
Rev. Med. Interne.
45
:
696
–
702
.
https://doi.org/10.1016/j.revmed.2024.05.003
Google Scholar
Crossref
Search ADS
PubMed
 
114.
Willemsen
,
M.
,
W.
Roosens
,
F.
Staels
,
T.H.M.
Schoonbrood
, and
R.
Schrijvers
.
2024
.
NLRC4-associated autoinflammatory disease: Insights from mouse models and somatic variants
.
J. Allergy Clin. Immunol.
155
:
803
–
807
.
https://doi.org/10.1016/j.jaci.2024.12.1076
Google Scholar
Crossref
Search ADS
PubMed
 
115.
Van Horebeek
,
L.
,
B.
Dubois
, and
A.
Goris
.
2019
.
Somatic variants: New kids on the block in human immunogenetics
.
Trends Genet.
35
:
935
–
947
.
https://doi.org/10.1016/j.tig.2019.09.005
Google Scholar
Crossref
Search ADS
PubMed
 
116.
Conrad
,
N.
,
S.
Misra
,
J.Y.
Verbakel
,
G.
Verbeke
,
G.
Molenberghs
,
P.N.
Taylor
,
J.
Mason
,
N.
Sattar
,
J.J.V.
McMurray
,
I.B.
McInnes
, et al.
2023
.
Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: A population-based cohort study of 22 million individuals in the UK
.
Lancet
.
401
:
1878
–
1890
.
https://doi.org/10.1016/S0140-6736(23)00457-9
Google Scholar
Crossref
Search ADS
PubMed
 
117.
Brown
,
G.J.
,
P.F.
Cañete
,
H.
Wang
,
A.
Medhavy
,
J.
Bones
,
J.A.
Roco
,
Y.
He
,
Y.
Qin
,
J.
Cappello
,
J.I.
Ellyard
, et al.
2022
.
TLR7 gain-of-function genetic variation causes human lupus
.
Nature
.
605
:
349
–
356
.
https://doi.org/10.1038/s41586-022-04642-z
Google Scholar
Crossref
Search ADS
PubMed
 
118.
Nikolic
,
R.P.A.
, and
C.
Moran Toro
.
2023
.
Childhood-onset COPA syndrome recognized retrospectively in the context of polyarticular juvenile idiopathic arthritis and rheumatoid arthritis
.
Case Rep. Rheumatol.
2023
:
3240245
.
https://doi.org/10.1155/2023/3240245
Google Scholar
Crossref
Search ADS
PubMed
 
119.
Brehm
,
A.
,
Y.
Liu
,
A.
Sheikh
,
B.
Marrero
,
E.
Omoyinmi
,
Q.
Zhou
,
G.
Montealegre
,
A.
Biancotto
,
A.
Reinhardt
,
A.
Almeida de Jesus
, et al.
2015
.
Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production
.
J. Clin. Invest.
125
:
4196
–
4211
.
https://doi.org/10.1172/JCI81260
Google Scholar
Crossref
Search ADS
PubMed
 
120.
Kanazawa
,
N.
,
H.
Hemmi
,
N.
Kinjo
,
H.
Ohnishi
,
J.
Hamazaki
,
H.
Mishima
,
A.
Kinoshita
,
T.
Mizushima
,
S.
Hamada
,
K.
Hamada
, et al.
2021
.
Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency
.
Nat. Commun.
12
:
6819
.
https://doi.org/10.1038/s41467-021-27085-y
Google Scholar
Crossref
Search ADS
PubMed
 
121.
Niihori
,
T.
,
M.
Ouchi-Uchiyama
,
Y.
Sasahara
,
T.
Kaneko
,
Y.
Hashii
,
M.
Irie
,
A.
Sato
,
Y.
Saito-Nanjo
,
R.
Funayama
,
T.
Nagashima
, et al.
2015
.
Mutations in MECOM, encoding oncoprotein EVI1, cause radioulnar synostosis with amegakaryocytic thrombocytopenia
.
Am. J. Hum. Genet.
97
:
848
–
854
.
https://doi.org/10.1016/j.ajhg.2015.10.010
Google Scholar
Crossref
Search ADS
PubMed
 
122.
Germeshausen
,
M.
,
P.
Ancliff
,
J.
Estrada
,
M.
Metzler
,
E.
Ponstingl
,
H.
Rütschle
,
D.
Schwabe
,
R.H.
Scott
,
S.
Unal
,
A.
Wawer
, et al.
2018
.
MECOM-Associated syndrome: A heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia
.
Blood Adv.
2
:
586
–
596
.
https://doi.org/10.1182/bloodadvances.2018016501
Google Scholar
Crossref
Search ADS
PubMed
 
123.
Bastard
,
P.
,
S.E.
Vazquez
,
J.
Liu
,
M.T.
Laurie
,
C.Y.
Wang
,
A.
Gervais
,
T.
Le Voyer
,
L.
Bizien
,
C.
Zamecnik
,
Q.
Philippot
, et al.
2023
.
Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
.
Sci. Immunol.
8
:eabp8966.
https://doi.org/10.1126/sciimmunol.abp8966
Google Scholar
 
124.
Lin
,
S.C.
,
F.R.
Zhao
,
H.
Janova
,
A.
Gervais
,
S.
Rucknagel
,
K.O.
Murray
,
J.L.
Casanova
, and
M.S.
Diamond
.
2023
.
Blockade of interferon signaling decreases gut barrier integrity and promotes severe West Nile virus disease
.
Nat. Commun.
14
:
5973
.
https://doi.org/10.1038/s41467-023-41600-3
Google Scholar
Crossref
Search ADS
PubMed
 
125.
Cheng
,
A.
,
A.
Kashyap
,
H.
Salvator
,
L.B.
Rosen
,
D.
Colby
,
F.
Ardeshir-Larijani
,
P.J.
Loehrer
,
L.
Ding
,
S.O.
Lugo Reyes
,
S.
Riminton
, et al.
2024
.
Anti-Interleukin-23 autoantibodies in adult-onset immunodeficiency
.
N. Engl. J. Med.
390
:
1105
–
1117
.
https://doi.org/10.1056/NEJMoa2210665
Google Scholar
Crossref
Search ADS
PubMed
 
126.
Casanova
,
J.-L.
2025
.
Human immunity
.
J. Hum. Immun
.
1
:
e20250001
.
https://doi.org/10.70962/jhi.20250001
Google Scholar
Crossref
Search ADS
 

Author notes

*

I. Meyts and S.G. Tangye contributed equally to this paper.

Disclosures: I. Aksentijevich reported “other” from In Vitro Diagnostic Solutions during the conduct of the study. T. Morio reported personal fees from Takeda Pharmaceutical, CSL Behring, Japan Blood Product Organization, Asteras, Sanofi, Ono Pharma, and Amgen outside the submitted work. K.E. Sullivan reported personal fees from Immune Deficiency Foundation during the conduct of the study. T.R. Torgerson reported personal fees from Pharming healthcare and Takeda, and “other” from Eli Lilly outside the submitted work. I. Meyts reported grants from CSL Behring, Takeda, and Octapharma, and “other” from Boehringer-Ingelheim outside the submitted work. No other disclosures were reported.

© 2025 Poli et al.
2025
This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by-nd/4.0/).
This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License .
Attribution-NoDerivatives