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).

[ViewLarge]
This Feature Is Available To Subscribers Only

or Create an Account

Close Modal
Close Modal