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.

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