Version June 2024
| Disease | Genetic defect | Inheritance | OMIM | Circulating T cells | Circulating B cells | Functional defect | Associated features |
| Familial hemophagocytic lymphohistiocytosis (FHL syndromes) | |||||||
| Perforin deficiency (FHL2) | Perforin 1 (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) | Unc-13 homolog D (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) | Syntaxin 11 (STX11) | AR | 605014 | Increased activated T cells | Normal | Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) | Fever, HSM, HLH, cytopenias |
| STXBP/Munc18-2 deficiency (FHL5) | Syntaxin binding protein 2 (STXBP2) | AR or AD | 601717 | Increased activated T cells | Normal | Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) | Fever, HSM, HLH, cytopenias |
| FAAP24 deficiency | FA core complex-associated protein 24 (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 | Solute carrier family 7 member 7 (SLC7A7) | AR | 222700 | Normal | Normal | Hyperinflammatory response to macrophages; normal NK cell function | Lysinuric protein intolerance, bleeding tendency, alveolar proteinosis |
| RHOG deficiency | Ras homolog family member G (RHOG) | AR | Normal | Slightly reduced | Impaired CTL and NK cell cytotoxicity | HLH, hemophagocytosis, HSM, fever, cytopenias, low hemoglobin, hypertriglyceridemia, elevated ferritin, sCD25 | |
| FHL syndromes with hypopigmentation | |||||||
| Chediak-Higashi syndrome | Lysosomal trafficking regulator (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 neurologic dysfunction |
| Griscelli syndrome, type 2 | RAB27A, member RAS oncogene family (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 | Adaptor-related protein complex 3 subunit beta 1 (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 | Adaptor-related protein complex 3 subunit delta 1 (AP3D1) | AR | 617050 | Normal | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss, neurodevelopmental delay |
| CEBPE neofunction | CCAAT enhancer binding protein epsilon (CEBPE) | AR GOF | 245480 | Mild reduction | Not one | Autoinflammatory activation/increased IFN gene expression; altered chromatin occupancy of mutant CEBPE; transcriptional changes | Recurrent abdominal pain, aseptic fever, systemic inflammation, abscesses, ulceration, infections, mild bleeding diathesis |
| Regulatory T cell defects | |||||||
| Immune dysregulation, polyendocrinopathy, enteropathy X linked (IPEX) | Forkhead box P3 (FOXP3) | XL | 300292 | Normal | Normal | Lack of and/or impaired function of CD4+ CD25+ FOXP3+ Tregs | Autoimmune enteropathy, early-onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema, elevated IgE and IgA |
| CD25 deficiency | IL-2 receptor subunit alpha (IL2RA) | AR | 147730 | Normal to decreased | Normal | No CD4+ CD25+ cells with impaired function of Tregs | Lymphoproliferation, autoimmunity, impaired T cell proliferation in vitro |
| C122 deficiency | IL-2 receptor subunit beta (IL2RB) | AR | 618495 | Increased memory CD8 T cells; decreased Tregs | Increased memory B cells | Diminished IL2R-beta expression; dysregulated signaling in response to IL-2/IL-15; increased immature NK cells | Lymphoproliferation, lymphadenopathy, HSM, AIHA, dermatitis, enteropathy, hypergammaglobulinemia, recurrent viral infections (EBV, CMV) |
| CTLA4 haploinsufficiency (ALPS-V) | Cytotoxic T lymphocyte-associated protein 4 (CTLA4) | AD | 123890 | Decreased | Decreased | Impaired function of Tregs | Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration, recurrent infections |
| LRBA deficiency | LPS-responsive beige-like anchor protein (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, IBD, autoimmunity |
| DEF6 deficiency | DEF6 guanine nucleotide exchange factor (DEF6) | AR | 610094 | Mild CD4 and CD8 lymphopenia | Low or normal numbers of B cells | Impaired Treg function | Enteropathy, HSM, cardiomyopathy, recurrent infections |
| STAT3 GOF mutation | Signal transducer and activator of transcription 3 (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 | BTB domain and CNC homolog 2 (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 | FERM domain-containing kindlin 1 (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 | IKAROS family zinc finger 1 (IKZF1) | AD GOF | 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 | |
| Autoimmunity with or without lymphoproliferation | |||||||
| Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED; APS-1) | Autoimmune regulator (AIRE) | AR or AD | 240300 | Normal | Normal | AIRE serves as the 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 | Itchy E3 ubiquitin protein ligase (ITCH) | AR | 606409 | Not assessed | Not assessed | 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 | Tripeptidyl peptidase 2 (TPP2) | AR | 190470 | Decreased | Decreased | Premature immunosenescence and immune dysregulation | Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections |
| JAK1 GOF | Janus kinase 1 (JAK1) | AD GOF | 147795 | Not assessed | Not assessed | Hyperactive JAK1 | HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections |
| Prolidase deficiency | Peptidase D (PEPD) | AR | 613230 | Normal | Normal | Peptidase D | Autoantibodies common, chronic skin ulcers, eczema, infections |
| SOCS1 haploinsufficiency | Suppressor of cytokine signaling 1 (SOCS1) | AD | 619375 | Decreased | Reduced switched memory B cells | Increased pSTAT1; increased type I/II IFN signature | Early-onset severe multisystemic autoimmunity, neutropenia, lymphopenia, ITP, AIHA, SLE, GN, HSM, psoriasis, arthritis, thyroiditis, hepatitis, recurrent bacterial infections, incomplete penetrance |
| PD-1 deficiency | Programmed cell death 1 (PDCD1) | AR | Mostly intact | Normal | Lack of PD-1 on patient PBMCs; reduced IFN-gamma production in response to mycobacterial stimuli | Tuberculosis, autoimmunity (type 1 diabetes, hypothyroidism, JIA), fatal pulmonary autoimmunity, HSM | |
| Immune dysregulation with colitis | |||||||
| IL-10 deficiency | Interleukin 10 (IL10) | AR | 124092 | Normal | Normal | No functional IL-10 secretion | IBD, folliculitis, recurrent respiratory diseases, arthritis |
| IL-10R deficiency | Interleukin 10 receptor subunit alpha (IL10RA) | AR | 146933 | Normal | Normal | Leukocytes unresponsive to IL-10 | IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma |
| Interleukin 10 receptor subunit beta (IL10RB) | AR | 123889 | Normal | Normal | Leukocytes unresponsive to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29 | IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma | |
| NFAT5 haploinsufficiency | Nuclear factor of activated T cells 5 (NFAT5) | AD | 604708 | Normal | Normal | Decreased memory B cells and plasmablasts | IBD, recurrent sinopulmonary infections |
| TGFB1 deficiency | Transforming growth factor beta 1 (TGFB1) | AR | 618213 | Normal | Normal | Decreased T cell proliferation in response to anti-CD3 | IBD, immunodeficiency, recurrent viral infections, microcephaly, encephalopathy |
| RIPK1 | Receptor interacting serine/threonine kinase 1 (RIPK1) | AR | 618108 | Reduced | Normal/reduced | Reduced activation of MAPK and NFkB pathways | Recurrent infections, early-onset IBD, progressive polyarthritis |
| ELF4 deficiency | E74-like ETS transcription factor 4 (ELF4) | XL | 301074 | Normal | Normal | Hyperinflammatory macrophages | Early-onset IBD/mucosal autoinflammation; fever; ulcers; responded to IL-1, TNF, or IIL-12p40 blockage |
| Autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome) | |||||||
| ALPS-FAS | TNF receptor superfamily member 6b (TNFRSF6) | AR or AD | 134637 | Increased TCR alpha-beta+ CD4–CD8– 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, and vitamin B12 |
| ALPS-FASLG | Fas ligand (FASLG) | AR | 134638 | Increased DN T cells | Normal | Apoptosis defect FasL mediated | Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated |
| ALPS-caspase 10 | Caspase 10 (CASP10) | AD | 601762 | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Adenopathies, splenomegaly, autoimmunity |
| ALPS-caspase 8 | Caspase 8 (CASP8) | AR | 601763 | Slightly increased N T cells | Normal | Defective lymphocyte apoptosis and activation | Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia |
| FADD deficiency | Fas associated via death domain (FADD) | AR | 602457 | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction |
| Susceptibility to EBV and lymphoproliferative conditions | |||||||
| SAP deficiency (XLP1) | SH2 domain-containing 1A (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 anemia, lymphoma, hypogammaglobulinemia, absent iNKT cells |
| XIAP deficiency (XLP2) | X-linked inhibitor of apoptosis (XIAP) | XL | 300079 | Normal or increased activated T cells; low/normal iNKT cells | Normal or reduced memory B cells | Increased T cells; susceptibility to apoptosis to CD95 and enhanced AICD | EBV infection, splenomegaly, lymphoproliferation, HLH, colitis, IB, hepatitis, low iNKT cells |
| CD27 deficiency | CD27 molecule (CD27) | AR | 615122 | Normal | No memory B cells | Hypogammaglobulinemia, poor antibody responses to some vaccines/infections | Features trigged by EBV infection, HLH, aplastic anemia, low iNKT cells, B lymphoma |
| CD70 deficiency | CD70 molecule (CD70) | AR | 602840 | Normal number; low Treg; poor activation and function | Decreased memory B cells | Hypogammaglobulinemia; poor antibody responses to some vaccines/infections | EBV susceptibility, Hodgkin lymphoma, autoimmunity in some patients |
| CTPS1 deficiency | CTP synthase 1 (CTPS1) | AR | 615897 | Normal to low, but reduced activation and 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) | TNF receptor superfamily member 9 (TNFRSF9) | AR | 602250 | Normal | Normal | Low IgG and IgA; poor responses to T cell-dependent and T cell-independent antigens; decreased T cell proliferation; IFN-gamma secretion; cytotoxicity | EBV lymphoproliferation, B cell lymphoma, chronic active EBV infection |
| RASGRP1 deficiency | RAS guanyl-releasing protein 1 (RASGRP1) | AR | 603962 | Poor activation, proliferation, and motility; reduced naïve T cells | Poor activation, proliferation, and motility | Normal IgM and IgG; increased IgA | Recurrent pneumonia, herpesvirus infections, EBV-associated lymphoma, decreased NK cell function |
| RLTPR deficiency | Capping protein regulator and myosin 1 linker 2 (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) | Magnesium transporter 1 (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 impaired expression of NKG2D | EBV infection, lymphoma, viral infections, respiratory and GI infections, glycosylation defects |
| PRKCD deficiency | Protein kinase C delta (PRKCD) | AR | 615559 | Normal | Low memory B cells; high CD5 B cells | Apoptotic defects in B cells | Recurrent infections, EBV chronic infection, lymphoproliferation, SLE-like autoimmunity (nephrotic and antiphospholipid syndromes), low IgG |
| TET2 deficiency | Tet methylcytosine dioxygenase 2 (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, HSM, autoimmunity, B lymphoma, failure to thrive, developmental delay |
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