Version May 2024
| Disease | Genetic defect | Inheritance | OMIM | Affected cells | Affected function | Associated features |
| Mendelian susceptibility to mycobacterial disease (MSMD) | ||||||
| IL-12 and IL-23 receptor beta 1 chain deficiency | Interleukin 12 receptor subunit beta 1 (IL12RB1) | AR | 601604 | Lymphocytes, NK cells | IFN-gamma secretion | Susceptibility to mycobacteria and Salmonella |
| IL-12p40 (IL-12 and IL-23) deficiency | Interleukin 12B (IL12B) | AR | 161561 | Monocytes | IFN-gamma secretion | Susceptibility to mycobacteria and Salmonella |
| IL-12 receptor beta 2 deficiency | Interleukin 12 receptor subunit beta 2 (IL12RB2) | AR | 601642 | Lymphocytes, NK cells | IFN-gamma secretion | Susceptibility to mycobacteria and Salmonella |
| IL-23R deficiency | Interleukin 23 receptor (IL23R) | AR | 607562 | Lymphocytes, NK cells | IFN-gamma secretion | Susceptibility to mycobacteria and Salmonella |
| IFN-gamma receptor 1 deficiency | Interferon gamma receptor 1 (IFNGR1) | AR | 209950 | Monocytes, lymphocytes | IFN-gamma binding and signaling | Susceptibility to mycobacteria and Salmonella |
| AD | 615978 | Monocytes, lymphocytes | IFN-gamma binding and signaling | Susceptibility to mycobacteria and Salmonella | ||
| IFN-gamma receptor 2 deficiency | Interferon gamma receptor 2 (IFNGR2) | AR | 147569 | Monocytes, lymphocytes | IFN-gamma signaling | Susceptibility to mycobacteria and Salmonella |
| STAT1 deficiency | Signal transducer and activator of transcription 1 (STAT1) | AD LOF | 614892 | Monocytes, lymphocytes | IFN-gamma signaling | Susceptibility to mycobacteria and Salmonella |
| Macrophage gp91 phox deficiency | Cytochrome b-245 beta chain (CYBB) | XL | 300645 | Macrophage only | Killing (faulty O2+) production | Isolated susceptibility to mycobacteria |
| IRF8 deficiency | Interferon regulatory factor 8 (IRF8) | AD | 614893 | Monocytes, lymphocytes | Impaired development of cDCs and Th1+ cells | Susceptibility to mycobacterial |
| AR | 226990 | Monocytes | Lack of circulating monocytes and DCs; reduced NK cell numbers and function reported in some patients | Susceptibility to mycobacterial and multiple other infectious agents including EBV | ||
| SPPL2a deficiency | Signal peptide peptidase-like 2A (SPPL2A) | AR | 608238 | Monocytes, lymphocytes | Impaired development of cDCs and Th1+ cells | Susceptibility to mycobacterial and Salmonella |
| Tyk2 deficiency | Tyrosine kinase 2 (TYK2) | AR | 611521 | Monocytes, lymphocytes | 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 | Tyrosine kinase 2 (TYK2) | AR | 176941 | Lymphocytes | Impaired cellular response to IL-23 | MSMD or tuberculosis |
| ISG15 deficiency | ISG15 ubiquitin-like modifier (ISG15) | AR | 147571 | IFN-gamma production defect | Susceptibility to mycobacteria (BCG), brain calcification | |
| ROR-gamma-t deficiency | RAR-related orphan receptor C (RORC) | AR | 602943 | Lymphocytes, NK cells | Lack of functional ROR-gamma-T protein; IFN-gamma production defect; complete absence of IL-17A/F-producing T cells | Susceptibility to mycobacteria and Candida |
| JAK1 deficiency | Janus kinase 1 (JAK1) | AR LOF | 147795 | Neutrophils, lymphocytes | Reduced JAK1 activation to cytokines; reduced IFN-gamma production | Susceptibility to mycobacteria and viruses, urothelial carcinoma |
| T-bet deficiency | T-box transcription factor 21 (TBX21) | AR | 619630 | Lymphocytes | Decreased IFN-gamma and TNF-alpha production by gamma-delta T cells, MAIT cells, iNKT cells, NK cells, and CD4+ T cells | Susceptibility to mycobacteria |
| IFN-gamma deficiency | Interferon gamma (IFNG) | AR | 618963 | Lymphocytes | No IFN-gamma production by patient T and NK cells | Susceptibility to mycobacteria |
| Epidermodysplasia verruciformis (HPV) | ||||||
| EVER1 deficiency | Transmembrane channel-like 6 (TMC6) | AR | 605828 | Keratinocytes | EVER1, EVER2, and CIB1 form a complex in keratinocytes | HPV (group B1) infections and cancer of the skin (typical epidermodysplasia verruciformis) |
| EVER2 deficiency | Transmembrane channel-like 8 (TMC8) | AR | 605829 | Keratinocytes | EVER1, EVER2, and CIB1 form a complex in keratinocytes | HPV (group B1) infections and cancer of the skin (typical epidermodysplasia verruciformis) |
| CIB1 deficiency | Calcium and integrin binding 1 (CIB1) | AR | 618267 | Keratinocytes | EVER1, EVER2, and CIB1 form a complex in keratinocytes | HPV (group B1) infections and cancer of the skin (typical epidermodysplasia verruciformis) |
| WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome | C-X-C motif chemokine receptor 4 (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 |
| Predisposition to severe viral infection | ||||||
| STAT1 deficiency | Signal transducer and activator of transcription 1 (STAT1) | AR LOF | 600555 | Leukocytes and other cells | STAT1-dependent IFN-alpha/beta, gamma, and delta responses | Severe viral infections, mycobacterial infection |
| STAT2 deficiency | Signal transducer and activator of transcription 2 (STAT2) | AR | 600556 | Leukocytes and other cells | STAT2-dependent IFN-alpha/beta and delta responses | Severe viral infections (disseminated vaccine-strain measles) |
| IRF9 deficiency | Interferon regulatory factor 9 (IRF9) | AR | 147574 | Leukocytes and other cells | IRF9- and ISGF3-dependent IFN-alpha/beta and delta responses | Severe influenza disease |
| IRF7 deficiency | Interferon regulatory factor 7 (IRF7) | AR | 605047 | Leukocytes, plasmacytoid DCs, nonhematopoietic cells | IFN-alpha, beta, and gamma production and IFN-delta production | Severe influenza disease |
| IFNAR1 deficiency | Interferon alpha and beta receptor subunit 1 (IFNAR1) | AR | 107450 | Leukocytes and other cells | IFNAR1-dependent responses to IFN-alpha/beta | Severe disease cause by yellow fever vaccine and measles vaccine |
| IFNAR2 deficiency | Interferon alpha and beta receptor subunit 2 (IFNAR2) | AR | 602376 | Broadly expressed | IFNAR2-depnent responses to IFN-alpha/beta | Severe viral infections (disseminated vaccine-strain measles, HHV6) |
| CD16 deficiency | Fc gamma receptor IIIa (FCGR3A) | AR | 146740 | NK cells | Altered NK cell function | Severe herpes virus infections, particularly VZV, EBV, and HPV |
| MDA5 deficiency | Interferon induced with helicase C domain 1 (IFIH1) | AR LOF | 606951 | Broadly expressed | Viral recognition and IFN induction | Rhinovirus and other RNA viruses |
| NOS2 deficiency | Nitric oxide synthase 2 (NOS2) | AR | 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 herpes virus (EBV, VZV, HSV) | |
| ZNFX1 deficiency | Zinc finger NFX1-type containing 1 (ZNFX1) | AR | 619644 | Broadly expressed | Increased 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 | RNA polymerase III subunit A (POLR3A) | AD | 614258 | Leukocytes and other cells | Impaired viral recognition and IFN induction in response to VZV or poly(I:C) | Severe VZV infection |
| RNA polymerase III subunit C (POLR3C) | AD | 617454 | Leukocytes and other cells | Impaired viral recognition and IFN induction in response to VZV or poly(I:C) | Severe VZV infection | |
| RNA polymerase III subunit F (POLR3F) | AD | 617455 | Leukocytes and other cells | Impaired viral recognition and IFN induction in response to VZV or poly(I:C) | Severe VZV infection | |
| Herpes simplex encephalitis (HSE) | ||||||
| TLR3 deficiency | Toll-like receptor 3 (TLR3) | AD or AR | 613002 | CNS resident cells and fibroblasts | TLR3-dependent IFN-alpha, beta, and gamma response | HSV1 encephalitis (incomplete clinical penetrance for all etiologies listed here), severe pulmonary influenza, VZV |
| UNC93B1 deficiency | Unc-93 homolog B1, TLR signaling regulator (UNC93B1) | AR | 608204 | CNS resident cells and fibroblasts | UNC93B-dependent IFN-alpha, beta, and gamma response | HSV1 encephalitis |
| TRAF3 deficiency | TNF receptor-associated factor 3 (TRAF3) | AD | 601896 | CNS resident cells and fibroblasts | TRAF3-dependent IFN-alpha, beta, and gamma response | HSV1 encephalitis |
| TRIF deficiency | TIR domain-containing adaptor molecule 1 (TICAM1) | AD or AR | 607601 | CNS resident cells and fibroblasts | TRIF-dependent IFN-alpha, beta, and gamma response | HSV1 encephalitis |
| TBK1 deficiency | TANK-binding kinase 1 (TBK1) | AD | 604834 | CNS resident cells and fibroblasts | TBK1-dependent IFN-alpha, beta, and gamma response | HSV1 encephalitis |
| IRF3 deficiency | Interferon regulatory factor 3 (IRF3) | AD | 616532 | CNS resident cells and fibroblasts | Low IFN-alpha/beta production in response to HSV1 and decreased IRF3 phosphorylation | HSV1 encephalitis |
| DBR1 deficiency | Debranching RNA lariats 1 (DBR1) | AR | 607024 | CNS resident cells and fibroblasts | Impaired production of antiviral IFNs | HSE of the brainstem, other viral infections of the brainstem |
| SNORA31 deficiency | Small nucleolar RNA, H/ACA box 31 (SNORA31) | AD | 619396 | CNS resident cells and fibroblasts | Impaired production of antiviral IFNs | Forebrain HSV1 encephalitis |
| ATG4A deficiency | Autophagy-related 4A cysteine peptidase (ATG4A) | AD | CNS resident cells and fibroblasts | Impaired HSV2-induced autophagy leading to increased viral replication and apoptosis of patient fibroblasts | Mollaret meningitis (recurrent lymphocytic meningitis) due to HSV2 | |
| MAP1LC3B2 deficiency | Microtubule-associated protein 1 light chain 3 beta 2 (MAP1LC3B2) | AD | CNS resident cells and fibroblasts | Impaired HSV2-induced autophagy leading to increased viral replication and apoptosis of patient fibroblasts | Mollaret meningitis (recurrent lymphocytic meningitis) due to HSV2 | |
| Predisposition to invasive fungal diseases | ||||||
| CARD9 deficiency | Caspase recruitment domain family member 9 (CARD9) | AR | 607212 | Mononuclear phagocytes | CARD9 signaling pathway | Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections |
| Predisposition to mucocutaneous candidiasis | ||||||
| IL-17RA deficiency | Interleukin 17 receptor A (IL17RA) | AR | 605461 | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RA signaling pathway | CMC, folliculitis |
| IL-17RC deficiency | Interleukin 17 receptor C (IL17RC) | AR | 610925 | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RC signaling pathway | CMC |
| IL-17F deficiency | Interleukin 17F (IL17F) | AD | 606496 | T cells | IL-17F-containing dimers | CMC, folliculitis |
| STAT1 GOF | Signal transducer and activator of transcription 1 (STAT1) | AD GOF | 600555 | T cells, B cells, monocytes | GOF STAT1 mutations that impair the development of IL-17-producing T cells | CMC; various fungal, bacterial, and viral (HSV) infections; autoimmunity (thyroiditis, diabetes, cytopenias); enteropathy |
| ACT1 deficiency | TRAF3 interacting protein 1 (TRAF3IP1) | AR | 607043 | T cells, fibroblasts | Fibroblasts fail to response to IL-17A and IL-17F and their T cells to IL-17E | CMC, blepharitis, folliculitis and macroglossia |
| JNK1 haploinsufficiency | Mitogen-activated protein kinase 8 (MAPK8) | AD | T cells, fibroblasts | Decreased Th17 cells ex vivo and in vitro; decreased responses of fibroblasts to IL-17A an IL-17F; decreased c-Jun/ATF2-dependent TGF-beta signalling | CMC, connective issue disorder (similar to Ehlers-Danlos syndrome) | |
| TLR signaling pathway deficiency with bacterial susceptibility | ||||||
| IRAK4 deficiency | Interleukin 1 receptor-associated kinase 4 (IRAK4) | AR | 606883 | Lymphocytes, granulocytes, monocytes | TIR-IRAK4 signaling pathway | Bacterial infections (pyogenes) |
| MyD88 deficiency | MYD88 innate immune signal transduction adaptor (MYD88) | AR | 602170 | Lymphocytes, granulocytes, monocytes | TIR-MyD88 signaling pathway | Bacterial infections (pyogenes) |
| IRAK1 deficiency | Interleukin 1 receptor-associated kinase 1 (IRAK1) | XL | 300283 | Lymphocytes, granulocytes, monocytes | TIR-IRAK1 signaling pathway | Bacterial infections, XL MECP2 deficiency-related syndrome due to large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 |
| TIRAP deficiency | TIR domain-containing adaptor protein (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 |
| TLR7 deficiency | Toll-like receptor 7 (TLR7) | XL | 301051 | Lymphocytes, myeloid cells | Impaired responses to TLR7 ligands; reduced production of type 1 IFN | Severe COVID-19 infection |
| TLR8 GOF | Toll-like receptor 8 (TLR8) | XL | 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 | |
| Other IEI related to nonhematopoietic tissues | ||||||
| Isolated congenital asplenia (ICA) | Ribosomal protein SA (RPSA) | AD | 271400 | No spleen | RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome | Bacteremia (encapsulated bacteria) |
| Heme oxygenase 1 (HMOX) | AR | 141250 | Macrophages | HMOX regulates iron recycling, and heme-dependent damage occurs | Hemolysis, nephritis, inflammation | |
| Trypanosomiasis | Apolipoprotein L1 (APOL1) | AD | 603743 | Somatic | Pore-forming serum protein | Trypanosomiasis |
| Acute liver failure due to NBAS deficiency | NBAS subunit of NRZ tethering complex (NBAS) | AR | 608025 | Somatic and hematopoietic | ER stress | Fever induces liver failure |
| Acute necrotizing encephalopathy | RAN-binding protein 2 (RANBP2) | AR | 601181 | Ubiquitous expression | Nuclear poor | Fever induces acute encephalopathy |
| Osteopetrosis | Chloride voltage-gated channel 7 (CLCN7) | AR | 602727 | Osteoclasts | Secretory lysosomes | Osteopetrosis with hypocalcemia, neurologic features |
| Sorting nexin 10 (SNX10) | AR | 614780 | Osteoclasts | Secretory lysosomes | Osteopetrosis with visual impairment | |
| Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) | AR | 607649 | Osteoclasts | Secretory lysosomes | Osteopetrosis with hypocalcemia, neurologic features | |
| Pleckstrin homology and RUN domain-containing M1 (PLEKHM1) | AR | 611466 | Osteoclasts | Secretory lysosomes | Osteopetrosis | |
| T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 (TCIRG1) | AR | 604592 | Osteoclasts | Secretory lysosomes | Osteopetrosis with hypocalcemia | |
| TNF receptor superfamily member 11a (TNFRSF11A) | AR | 603499 | Osteoclasts | Osteoclastogenesis | Osteopetrosis | |
| TNF superfamily member 11 (TNFSF11) | AR | 602642 | Stromal | Osteoclastogenesis | Osteopetrosis with severe growth retardation | |
| Hidradenitis suppurativa | Nicastrin (NCSTN) | AD | 605254 | Epidermis | Notch signaling/gamma-secretase in hair follicle regulates keratinization | Verneuil's disease/hidradenitis suppurativa with acne |
| Presenilin (PSEN) | AD | 613737 | Epidermis | Notch signaling/gamma-secretase in hair follicle regulates keratinization | Verneuil's disease/hidradenitis suppurativa with cutaneous hyperpigmentation | |
| Presenilin enhancer, gamma-secretase subunit (PSENEN) | AD | 613736 | Epidermis | Notch signaling/gamma-secretase in hair follicle regulates keratinization | Verneuil's disease/hidradenitis suppurativa | |
| Other IEI related to leukocytes | ||||||
| IRF4 haploinsufficiency | Interferon regulatory factor 4 (IRF4) | AD | 601900 | Lymphocytes, monocytes | IRF4 is a pleiotropic transcription factor | Whipple's disease |
| IL-18BP deficiency | Interleukin 18 binding protein (IL18BP) | AR | 604113 | Leukocytes and other cells | IL-18BP neutralizes secreted IL-18 | Fulminant viral hepatitis |
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