Врожденные ошибки иммунитета или, как их было принято называть ранее, первичные иммунодефициты – стремительно расширяющийся класс болезней, объединяющий самую разнообразную врожденную патологию, которая может проявляться в любом возрасте и в любой симптоматике. Для этих болезней характерны клинические маски, вследствие чего время от дебюта болезни до постановки окончательного диагноза может занимать многие годы.
Эти пациенты встречаются врачу любой специализации, а молекулярные механизмы патологии затрагивают все органы и системы человека. Классификация представляет собой десять таблиц из более чем 500 синдромов и соответствующих им генов или хромосомных аномалий.
Представляем обновленную таблицу классификации Врожденных дефектов иммунитета (октябрь 2024) со страницы комитета по врожденным ошибкам иммунитета международного союза иммунологических обществ (IUIS) (скачать).
В отчете IUIS 2024 года классифицированы 508 генов и 17 фенокопий, связанных с врожденными нарушениями иммунитета, включая 67 новых моногенных дефектов и 2 фенокопии. Таблицы из оригинальной статьи от апреля 2025: Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.
Table 1. Immunodeficiencies affecting cellular and humoral immunity
| Disease | Genetic defect | Inheritance | OMIM | T cells | B cells | Ig | Associated 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 |
Footnotes:
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 ).
Table 2. CIDs with associated or syndromic features
| Disease | Genetic defect | Inheritance | OMIM | T cells | B cells | Ig | Associated features |
|---|---|---|---|---|---|---|---|
| 1. Immunodeficiency with congenital thrombocytopenia | |||||||
| Wiskott–Aldrich syndrome (WAS LOF) | WAS | XL | 300392 | Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3 | Normal numbers | Low IgM and antibody responses to polysaccharides, often high IgA and IgE | Thrombocytopenia with small platelets, eczema, recurrent bacterial/viral infections, bloody diarrhea, lymphoma, autoimmune disease, IgA nephropathy. Patients with XL-thrombocytopenia have later onset of complications and more favorable life expectancy but eventually develop similar complications as observed in WAS |
| WIP deficiency | WIPF1 | AR | 602357 | Reduced, defective lymphocyte responses to anti-CD3 | Normal or low | Normal, except for high IgE | Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea; WAS protein absent |
| Arp2/3-mediated filament branching defect | ARPC1B | AR | 604223 | Normal | Normal numbers | Normal except for high IgA and IgE | Mild thrombocytopenia with normal-sized platelets, recurrent invasive infections; colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia; defective Arp2/3 filament branching |
| IKZF2 DN (ICHAD syndrome) | IKZF2 | AD | 606234 | CD4 and CD8 T-cell lymphopenia with low TRECs | Normal to low | Normal or low. Response to vaccine antigen normal to low | Recurrent respiratory and ear infections, pneumonia, and chronic lung disease. Early-onset immune dysregulation (atopic dermatitis and AIHA) and syndromic features including developmental delay, autism, sensorineural hearing loss, cleft palate and syndromic craniofacial features, abnormal teeth, athelia (absent nipples) |
| 2. DNA repair defects other than those listed in Table 1 | |||||||
| Ataxia–telangiectasia | ATM | AR | 607585 | Progressive decrease, poor proliferation to mitogens; may have low TRECs and T cells by NBS | Normal | Often low IgA, IgE, and IgG subclasses, increased IgM monomers; antibodies variably decreased | Ataxia, telangiectasia especially of sclerae; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein; increased radiosensitivity, chromosomal instability, and chromosomal translocations |
| Nijmegen breakage syndrome | NBN | AR | 602667 | Progressive decrease; may have low TRECs and T cells by NBS | Variably reduced | Often low IgA, IgE, and IgG subclasses, increased IgM; antibodies variably decreased | Microcephaly, dysmorphic facies; lymphomas and solid tumors; increased radiosensitivity; chromosomal instability |
| Bloom syndrome | BLM | AR | 604610 | Normal | Normal | Low | Short stature, dysmorphic facies, sun-sensitive erythema; marrow failure; leukemia, lymphoma; chromosomal instability |
| Immunodeficiency with centromeric instability and facial anomalies (ICF types 1, 2, 3, 4) | DNMT3B | AR | 602900 | Decreased or normal, responses to PHA may be decreased | Decreased or normal | Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency | Facial dysmorphic features, developmental delay, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 |
| ZBTB24 | AR | 614064 | Decreased or normal | Facial dysmorphic features, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 | |||
| CDCA7 | AR | 609937 | Decreased or normal; responses to PHA may be decreased | ||||
| HELLS | AR | 603946 | Decreased or normal | ||||
| PMS2 deficiency | PMS2 | AR | 600259 | Normal | Low B cells, switched and nonswitched | Low IgG and IgA, high IgM, abnormal antibody responses | Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumors |
| RNF168 deficiency (radiosensitivity, immune deficiency, dysmorphic features, learning difficulties [RIDDLE] syndrome) | RNF168 | AR | 612688 | Normal | Normal | Low IgG or IgA | Short stature, mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity |
| MCM4 deficiency | MCM4 | AR | 602638 | Normal | Normal | Normal | NK cells: low number and function; viral infections (EBV, HSV, VZV); short stature; B-cell lymphoma; adrenal failure |
| X-linked reticulate pigmentary disorder (POLA1 deficiency) | POLA1 | XL | 301220 | Not assessed | Not assessed | Not assessed | Hyperpigmentation, characteristic facies, lung, and GI involvement. NK cell dysfunction. Recurrent viral infections. POLA1 is required for synthesis of cytosolic RNA:DNA; its deficiency leads to increased type I interferon; hypomorphic variants may present with hyperpigmentation and interferonopathy, without immunodeficiency |
| POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome) | POLE1 | AR | 174762 | Normal; decreased T-cell proliferation | Low memory B cells | Low IgG2 and IgM, lack of antibody to PPS | Recurrent respiratory infections, meningitis; facial dysmorphism, livedo, short stature |
| POLE2 (polymerase ε subunit 2) deficiency | POLE2 | AR | 602670 | Lymphopenia, lack of TRECS at NBS, absent proliferation in response to antigens | Very low | Hypogammaglobulinemia | Recurrent infections, disseminated BCG infections; autoimmunity (type 1 diabetes), hypothyroidism, facial dysmorphism |
| Ligase I deficiency | LIG1 | AR | 126391 | Lymphopenia, increased γδ T cells, decreased mitogen response | Normal | Hypogammaglobulinemia, Reduced antibody responses | Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells |
| NSMCE3 deficiency | NSMCE3 | AR | 608243 | Decreased number, poor responses to mitogens and antigens | Normal | Normal IgG, IgA, normal to elevated IgM; decreased antibody responses to PPS | Severe lung disease (possibly viral); thymic hypoplasia; chromosomal breakage, radiation sensitivity |
| ERCC6L2 (Hebo deficiency) | ERCC6L2 | AR | 615667 | Lymphopenia | Low | Normal | Facial dysmorphism, microcephaly; bone marrow failure |
| GINS1 deficiency | GINS1 | AR | 610608 | Low or normal | Low or normal | High IgA, low IgM, and IgG | Neutropenia; IUGR; NK cells very low |
| MCM10 deficiency | MCM10 | AR | 619313 | Low or normal | Low | Normal IgM, IgA, decreased IgG | Severe (fatal) CMV infection, HLH-like, phenocopies GINS1 and MCM4 deficiencies; ↓ NK cells and NK function |
| GINS4 deficiency | GINS4 | AR | 610611 | Normal | Normal | Normal or increased | Low NK cell numbers and function, neutropenia, recurrent infections including CMV and varicella, and recurrent herpes labialis; recurrent otitis, sinusitis, gingivitis and oral abscesses, pneumonia, gastrointestinal sepsis, intermittent diarrhea, intrauterine growth restriction, growth delay, cryptorchidism, tonsillar hypertrophy, recurrent fever |
| Rothmund–Thomson syndrome | RECQL4 | AR | 268400 | Normal or low | Normal or low | Normal or low | Variable immunodeficiency, recurrent infections, poikiloderma, hyperkeratosis, hair, skeletal dental, and gastrointestinal abnormalities, growth delay, increased cancer risk, especially osteosarcoma |
| 3. Thymic defects with additional congenital anomalies | |||||||
| DiGeorge/velocardiofacial syndrome Chromosome 22q11.2DS | Large deletion (3 Mb) typically in chromosome 22 (TBX1) | AD | 602054 | Decreased or normal, 5% have low TRECs at NBS and <1,500 CD3T cells/μl in neonatal period | Normal | Normal or decreased | Hypoparathyroidism; conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability, schizophrenia and autoimmunity |
| DiGeorge/velocardiofacial syndrome | Unknown | Sporadic | Decreased or normal | ||||
| TBX1 deficiency | TBX1 | AD | 602054 | Decreased or normal, may have low TRECs at NBS | |||
| CHARGE syndrome | CHD7 | AD | 608892 | Decreased or normal, may have low TRECs at NBS; response to PHA may be decreased | Normal | Normal or decreased | Coloboma of eye; heart anomaly; choanal atresia; intellectual disability; genital and ear anomalies, CNS malformation; some are SCID-like |
| SEMA3E | AD | 608166 | |||||
| Unknown | |||||||
| Winged-helix nude FOXN1 deficiency | FOXN1 | AR | 601705 | Very low | Normal | Decreased | Severe infections; abnormal thymic epithelium, immunodeficiency; congenital alopecia, nail dystrophy; neural tube defect |
| FOXN1 haploinsufficiency or GOF | FOXN1 | AD | 600838 | Severe T-cell lymphopenia at birth, normalized by adulthood | Normal/low | Not assessed | Recurrent, viral, and bacterial respiratory tract infections; skin involvement (eczema, dermatitis), nail dystrophy |
| Chromosome 10p13-p14 DS (10p13-p14DS) | Del10p13-p14 | AD | 601362 | Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens; hypoplastic thymus may be present | Normal | Normal | Hypoparathyroidism; renal disease; deafness; growth retardation; facial dysmorphism; cardiac defects may be present; recurrent infections +/- |
| 4. Immuno-osseous dysplasias | |||||||
| Cartilage hair hypoplasia (CHH) | RMRP | AR | 157660 | Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation | Normal | Normal or reduced, antibodies variably decreased | Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestine |
| Schimke immuno-osseous dysplasia | SMARCAL1 | AR | 606622 | Decreased | Normal | Normal | Short stature, spondyloepiphyseal dysplasia, IUGR; nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure |
| MYSM1 deficiency | MYSM1 | AR | 612176 | T-cell lymphopenia, reduced naïve T cells, low NK cells | B-cell deficiency | Hypogammaglobulinemia | Short stature; recurrent infections; congenital bone marrow failure, myelodysplasia; immunodeficiency affecting B cells and granulocytes; skeletal anomalies; cataracts; developmental delay |
| MOPD1 deficiency (Roifman syndrome) | RNU4ATAC | AR | 601428 | Decreased NK cell function | Decreased total and memory B cells | Hypogammaglobulinemia, variably decreased specific antibodies | Recurrent bacterial infections; lymphadenopathy; spondyloepiphyseal dysplasia, extreme IUGR; retinal dystrophy; facial dysmorphism; may present with microcephaly; short stature |
| Immunoskeletal dysplasia with neurodevelopmental abnormalities (EXTL3 deficiency) | EXTL3 | AR | 617425 | Decreased | Normal | Decreased or normal | Short stature; cervical spinal stenosis, neurodevelopmental impairment; eosinophilia; may have early infant mortality |
| 5. Syndromes associated with elevated IgE and/or atopic disease not listed elsewhere (hyper-IgE syndromes [HIES]) | |||||||
| AD-HIES STAT3 deficiency (Job syndrome) | STAT3 | AD LOF (dominant negative) | 147060 | Normal overall; Th17, T follicular helper, MAIT, NKT cells decreased, Tregs may be increased; impaired responses to STAT3-activating cytokines | Normal, reduced memory B cells, BAFF expression increased, impaired responses to STAT3-activating cytokines | Very high IgE, specific antibody production decreased | Distinctive facial features (broad nasal bridge); bacterial infections (boils, pulmonary abscesses, pneumatoceles) due to Staphylococcusaureus, secondary pulmonary aspergillosis, PJP; eczema, chronic mucocutaneous candidiasis (CMC); impaired acute phase response, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms |
| IL-6 receptor deficiency | IL6R | AR | 147880 | Normal/increased, increased memory Th2 cells; reduced proportions of cTFh cells; normal responses to mitogens | Normal total and memory B; reduced switched memory B | Normal/low serum IgM, IgG, A. Very high IgE; specific antibody production low | Atopic dermatitis (eczema), reduced inflammatory responses, recurrent skin and lung pyogenic bacterial infections, cold abscesses; high circulating IL-6 levels |
| IL-6 signal transducer (IL-6ST) partial deficiency | IL6ST | AR | 618523 | Normal Th17 cells | Reduced switched and nonswitched memory B cells | High IgE, specific antibody production variably affected | Eczema, bacterial infections, boils, recurrent respiratory tract infections (including pneumonia, bronchiectasis) pulmonary abscesses; eosinophilia; pneumatoceles; bone fractures; retention of primary teeth; craniosynostosis; scoliosis, impaired acute phase responses |
| AD | 619752 | Normal numbers but high naïve, low central memory T cells, and low proportion of effector memory CD8 T cells. Increased Th2, low frequencies of TFh and MAIT | Normal total but low memory | Normal IgM, G, A; hyper-IgE | Dermatitis/eczema, eosinophilia, recurrent skin infections, pneumonia, bronchiectasis, pneumatoceles with severe secondary pulmonary aspergillosis, connective tissue defects (scoliosis, face, joints, fractures, palate, tooth retention). Phenocopies aspects of AR IL-6R and IL-11R deficiencies (due to unresponsiveness to these cytokines), as well as AD STAT3 and AR ZNF341 | ||
| IL-6ST complete deficiency | IL6ST | AR | 619751 | ND; death in utero or in neonatal period occurred for most affected individuals | Fatal Stuve–Wiedemann-like syndrome; skeletal dysplasia, osteoporosis, hyperextensibility, lung dysfunction, renal abnormalities, thrombocytopenia, dermatitis, eczema. Defective acute phase response. Completely unresponsive to IL-6 family cytokines | ||
| ZNF341 deficiency AR-HIES | ZNF341 | AR | 618282 | Decreased Th17 proportion and low NK cell counts High frequencies of naïve CD4+T cells. Low frequencies of CD4+ and CD8+ CM T cells | Normal, reduced memory B cells, impaired responses to STAT3-activating cytokines | High IgE and IgG, normal or subnormal specific antibody production | Phenocopy of AD-HIES; atopic dermatitis/eczema, bacterial skin infections and abscesses (S. aureus), recurrent respiratory infections, lung abscesses and pneumatoceles; CMC; mild eosinophilia; mild facial dysmorphism; skeletal/connective tissue abnormalities (hyperextensible joints; bone fractures, retention of primary teeth) |
| ERBIN deficiency | ERBIN | AD | 606944 | Increased circulating Treg | Normal | Moderately increased IgE | Recurrent respiratory infections, susceptibility to S. aureus, eczema; hyperextensible joints, scoliosis; arterial dilatation in some patients |
| Loeys–Dietz syndrome (TGFBR deficiency) | TGFBR1 | AD | 609192 | Normal | Normal | Elevated IgE | Recurrent respiratory infections; eczema, food allergies; hyperextensible joints, scoliosis, retention of primary teeth; aortic aneurisms |
| TGFBR2 | 610168 | ||||||
| SMAD3 | 613795 | ||||||
| Comel–Netherton syndrome | SPINK5 | AR | 605010 | Normal | Normal numbers, low switched and nonswitched B cells | High IgE and IgA, antibody variably decreased | Congenital ichthyosis, bamboo hair, atopic diathesis; severe atopic manifestations, increased bacterial infections; failure to thrive |
| PGM3 deficiency | PGM3 | AR | 172100 | CD8 and CD4 T cells may be decreased | Low B and memory B cells | Normal or elevated IgG and IgA, most with high IgE, eosinophilia | Severe eczema; autoimmunity; bacterial (S. aureus) and viral infections; recurrent skin abscesses, otitis media, recurrent respiratory tract infection (pneumonia, bronchiectasis); candidiasis; eosinophilia; neutropenia; skeletal anomalies/dysplasia (joint hypermotility and aneurism formation): short stature, brachydactyly, dysmorphic facial features; mild intellectual disability and cognitive impairment, delayed CNS myelination in some affected individuals. Failure to thrive |
| CARD11 deficiency (heterozygous DN) | CARD11 | AD LOF | 617638 | Normal number, but defective T-cell activation and proliferation. Skewing toward Th2 | Normal to low | High IgE, poor specific antibody production; impaired activation of both NF-κB and mTORC1 pathways | Variable atopy, eczema, food allergies, eosinophilia; cutaneous viral infections, recurrent respiratory infections; lymphoma; CID |
| STAT6 GOF | STAT6 | AD GOF | 620532 | Normal numbers. T cells show Th2 skewing | Normal | High IgE, normal IgG | Early-onset severe allergic diseases, resistant atopic dermatitis, eosinophilic GI disease with reflux, dysphagia, and eosinophilic esophagitis, food allergies with anaphylaxis, asthma with interstitial lung disease and bronchiectasis. Eosinophilia. Recurrent skin and respiratory bacterial, viral, and fungal infections in ∼50%. Short stature, skeletal features |
| 6. Defects of vitamin B12 and folate metabolism | |||||||
| Transcobalamin 2 deficiency | TCN2 | AR | 613441 | Normal | Variable | Decreased | Megaloblastic anemia, pancytopenia; if untreated (B12) for prolonged periods results in intellectual disability |
| SLC46A1/PCFT deficiency causing hereditary folate malabsorption | SLC46A1 | AR | 229050 | Variable numbers and activation profile | Variable | Decreased | Megaloblastic anemia, failure to thrive; if untreated for prolonged periods results in intellectual disability |
| Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency | MTHFD1 | AR | 172460 | Low thymic output, normal in vitro proliferation | Low | Decreased/poor antibody responses to conjugated polysaccharide antigens | Recurrent bacterial infection, P. jirovecii; megaloblastic anemia; failure to thrive; neutropenia; seizures, intellectual disability; folate-responsive |
| SLC19A1/PCFT deficiency causing hereditary folate malabsorption | SLC19A1 | AR | 620603 | Mitogen-induced T-cell proliferation was significantly reduced | Slightly low | Slightly decreased or borderline | Recurrent infections, severe pneumonia, mucositis, megaloblastic folate–dependent anemia |
| 7. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID) | |||||||
| EDA-ID due to NEMO/IKBKG deficiency (ectodermal dysplasia, immune deficiency) | IKBKG | XL | 300248 | Normal or decreased, TCR activation impaired | Normal; low memory and isotype-switched B cells | Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibodies to polysaccharide antigens | Anhidrotic ectodermal dysplasia (in some); various infections (bacteria, mycobacteria, viruses, fungi); colitis; conical teeth, variable defects of skin, hair, and teeth; monocyte dysfunction |
| EDA-ID due to IKBA GOF mutation | NFKBIA | AD GOF | 164008 | Normal total T cells, TCR activation impaired | Normal B-cell numbers, impaired BCR activation, low memory and isotype-switched B cells | Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens | Anhidrotic ectodermal dysplasia. Various infections (bacteria, mycobacteria, viruses, fungi); colitis; variable defects of skin, hair, and teeth; T-cell and monocyte dysfunction |
| EDA-ID due to IKBKB GOF mutation | IKBKB | AD GOF | 618204 | Decreased T cells, impaired TCR activation | Normal number, poor function | Reduced | Recurrent bacterial, viral, fungal infections; variable ectodermal defects |
| 8. Calcium channel defects | |||||||
| ORAI-1 deficiency | ORAI1 | AR | 610277 | Normal, defective TCR–mediated activation | Normal | Normal | Autoimmunity; EDA; nonprogressive myopathy |
| STIM1 deficiency | STIM1 | AR | 605921 | ||||
| CRACR2A deficiency | CRACR2A | AR | NA | Mild reduction in T-cell numbers | Normal | Low | Later onset, chronic diarrhea, recurrent lower respiratory tract infections, including pneumonia |
| ITPR3 | ITPR3 | AR | NA | Low T-cell numbers, impaired T-cell activation and proliferation | Low. Trend to lower proliferation | Low | Charcot–Marie–Tooth in one patient. CID, ITP, AIHA. Recurrent infections, enteropathy |
| 9. Other defects | |||||||
| Purine nucleoside phosphorylase (PNP) deficiency | PNP | AR | 164050 | Progressive decrease | Normal | Normal or low | Autoimmune hemolytic anemia; neurological impairment |
| Immunodeficiency with multiple intestinal atresias | TTC7A | AR | 609332 | Variable, but sometimes absent or low TRECs at NBS; may have SCID phenotype at birth | Normal or low | Markedly decreased IgG, IgM, IgA | Bacterial (sepsis), fungal, viral infections; multiple intestinal atresias, often with intrauterine polyhydramnios and early demise |
| Trichohepatoenteric syndrome | TTC37 | AR | 222470 | Impaired IFN-γ production | Variably low numbers of switched memory B cells | Hypogammaglobulinemia, may have low antibody responses | Respiratory infections; IUGR; facial dysmorphic features, wooly hair; early-onset intractable diarrhea, liver cirrhosis; platelet abnormalities |
| SKIV2L | 614602 | ||||||
| VODI | SP110 | AR | 604457 | Normal (decreased memory T cells) | Normal (decreased memory B cells) | Decreased IgG, IgA, IgM, absent germinal center and tissue plasma cells | Hepatic veno-occlusive disease; susceptibility to PJP pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystrophy |
| BCL11B deficiency | BCL11B | AD | 617237 | Low, poor proliferation | Normal | Normal | Congenital abnormalities, neonatal teeth, dysmorphic facies; absent corpus callosum, neurocognitive deficits |
| EPG5 deficiency (Vici syndrome) | EPG5 | AR | 615068 | Profound depletion of CD4+ cells | Defective | Decreased (particularly IgG2) | Agenesis of the corpus callosum; cataracts; cardiomyopathy; skin hypopigmentation; intellectual disability; microcephaly; recurrent infections, chronic mucocutaneous candidiasis |
| HOIL1 deficiency | RBCK1 | AR | 610924 | Normal numbers | Normal, decreased memory B cells | Poor antibody responses to polysaccharides | Bacterial infections; autoinflammation; amylopectinosis |
| HOIP deficiency | RNF31 | AR | 612487 | Normal numbers | Normal, decreased memory B cells | Decreased | Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia |
| Hennekam lymphangiectasia–lymphedema syndrome | CCBE1 | AR | 612753 | Low/variable | Low/variable | Decreased | Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features |
| FAT4 | AR | 612411 | Low/variable | Low/variable | Decreased | Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features | |
| Activating de novo mutations in nuclear factor, erythroid 2–like (NFE2L2) | NFE2L2 | AD | 617744 | Not reported | Decreased switched memory B cells | Hypogammaglobulinemia, decreased antibody responses | Recurrent respiratory and skin infections; growth retardation, developmental delay; white matter cerebral lesions; increased level of homocysteine; increased expression of stress response genes |
| STAT5B deficiency | STAT5B | AR | 245590 | Modestly decreased, reduced Treg number and function | Normal | Hypergammaglobulinemia, increased IgE | Growth hormone–insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity |
| AD (dominant negative) | 604260 | Normal | Normal | Increased IgE | Growth failure; eczema (no immune defects compared with AR STAT5 deficiency) | ||
| Kabuki syndrome (types 1 and 2) | KMT2D | AD | 602113 | Normal | Normal | Low IgA and occasionally low IgG | Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature; intellectual disability; congenital heart defects; recurrent infections (otitis media, pneumonia) in 50% of patients; autoimmunity may be present |
| KDM6A | XL (females may be affected) | 300128 | |||||
| KMT2A deficiency (Wiedemann–Steiner syndrome) | KMT2A | AD | 605130 | Normal | Decreased switched and nonswitched memory B cells | Hypogammaglobulinemia, decreased antibody responses | Respiratory infections; short stature; hypertelorism; hairy elbows; developmental delay, intellectual disability |
| DIAPH1 deficiency | DIAPH1 | AR | 616632 | Reduced naïve T cells | Decreased memory B cells | Low IgM, normal IgG | Seizures, cortical blindness, microcephaly syndrome (SCBMS); recurrent bacterial, viral, fungal infections; B lymphoma (3/7) |
| AIOLOS deficiency | IKZF3 | AD | 619437 | Normal | Reduced; impaired development | Very low | EBV susceptibility, recurrent sinopulmonary and respiratory infections, P. jirovecii, warts (HPV), Mycobacterium avium, B-cell malignancy. Haploinsufficiency shows autoimmunity and allergy |
| CD28 deficiency | CD28 | AR | 620901 | Normal | Normal | Normal | Susceptibility to HPV infection only |
| SGPL1 deficiency | SGPL1 | AR | 617575 | Low | Low | Low maybe due to nephrotic syndrome | Low or normal NK cells. Multiple bacterial infections. Nephrotic syndrome, adrenal insufficiency, ichthyosis/acanthosis, dyslipidemia, mild hypothyroidism, neurological defects |
| PTCRA deficiency | PTCRA | AR | 620931 | Low T-cell counts in infancy. Total T-cell counts gradually increased to reach normal ranges. Low circulating naïve αβ T-cell counts, normal memory αβ T-cell counts and high naïve γδ T-cell counts, low TRECs | Normal | Recurrent infections, lymphoproliferation, and/or autoimmunity and presence of autoantibodies. Some (6/10) individuals are healthy, and some can have small or no visible thymus. Low frequency of MAIT. High proportion of CD4−CD8−DN αβ T cells among naïve T cells | |
| FLT3L deficiency | FLT3LG | AR | 620926 | Normal | Decreased | Increased | Hypoplastic anemia, monocytopenia, DC-penia, low/absence of dermal DCs. NK cells normal. Recurrent/persistent viral infections, severe warts, bacterial (pneumonia, otitis media, pharyngitis, cellulitis) and fungal infections. Recurrent diarrhea from early infancy, failure to thrive |
| Chromosome 11q DS (Jacobsen syndrome) | 11q23del | AD | 147791 | Lymphopenia; low NK cells | Decreased B cells and switched memory B cells | Hypogammaglobulinemia, decreased antibody responses | Recurrent respiratory infections; multiple warts; facial dysmorphism, growth retardation |
Footnotes:
EDA, ectodermal dysplasia, anhidrotic; HSV, herpes simplex virus; VZV, varicella zoster virus; BCG; bacillus Calmette–Guerin; NBS, newborn screen; TREC, T-cell receptor excision circle (biomarker for low T cells used in NBS); IUGR, intrauterine growth retardation ; CID, combined immune deficiency; ITP, idiopathic thrombocytopenic purpura; AIHA, autoimmune hemolytic anemia; SCID, severe combined immunodeficiency; CID, combined immunodeficiency; CNS, central nervous system; HIES, hyper-IgE syndromes; HPV, human papillomavirus; Ab, antibody; EDA-ID, ectodermodysplasia with immunodeficiency; PJP, Pneumocystis jirovecii pneumonia.
Total number of mutant genes in Table 2 : 83 including two entries for IL-6ST, two entries for STAT5B, and two for FOXN1 with distinct but partially overlapping phenotypes.
New IEIs: 10, dominant negative IKZF2 , GINS4 , STAT6 GOF, SMAD3 , SLC19A1 , SGPL1 , PTCRA , FLT3L , ITPR3 , and RECQL4 ( 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ).
Unknown cause of DiGeorge syndrome, unknown cause of CHARGE syndrome, unknown gene(s) within 10p13-14 deletion responsible for phenotype.
Table 3. Predominantly antibody deficiencies
| Disease | Genetic defect | Inheritance | OMIM | Ig | Associated features |
|---|---|---|---|---|---|
| 1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia | |||||
| BTK deficiency, X-linked agammaglobulinemia | BTK | XL | 300300 | All isotypes decreased in majority of patients; some patients have detectable immunoglobulins | Severe bacterial infections, normal numbers of pro-B cells |
| μ heavy chain deficiency | IGHM | AR | 147020 | All isotypes decreased | Severe bacterial infections, normal numbers of pro-B cells |
| λ5 deficiency | IGLL1 | AR | 146770 | ||
| Igα deficiency | CD79A | AR | 112205 | ||
| Igβ deficiency | CD79B | AR | 147245 | ||
| BLNK deficiency | BLNK | AR | 604515 | ||
| p110δ deficiency | PIK3CD | AR | 602839 | Severe bacterial infections; autoimmune complications (IBD) | |
| p85 deficiency | PIK3R1 | AR | 615214 | Severe bacterial infections, cytopenias, decreased or absent pro-B cells | |
| E47 transcription factor deficiency | TCF3 | AD | 616941 | Recurrent bacterial infections | |
| AR | 619824 | Severe, recurrent bacterial infections, failure to thrive | |||
| SLC39A7 (ZIP7) deficiency | SLC39A7 | AR | 601416 | Early-onset infections, blistering dermatosis, failure to thrive, thrombocytopenia | |
| Hoffman syndrome/TOP2B deficiency | TOP2B | AD | 126431 | Recurrent infections, facial dysmorphism, limb anomalies | |
| FNIP1 deficiency (6 patients) | FNIP1 | AR | 619705 | Early-onset recurrent infections, bronchiectasis, fibrosis, interstitial pneumonia; neutropenia (severe or intermittent); Crohn’s disease (one patient); congenital heart defects, muscular hypotonia; developmental delay | |
| PU1 deficiency | SPI1 | AD | 619707 | Sinopulmonary infections with encapsulated bacteria, viral infections | |
| PAX5 deficiency (n = 1) | PAX5 | AR | Early B-cell developmental block, B cell strongly decreased, transitional and naïve mature B cells expressed lower CD19 and IgD—natural effector and memory B cells, as well as plasmablasts, were absent in the blood of the patient; a-/hypo-gammaglobulinemia, recurrent infections, autism spectrum disorder (ASD), and sensorimotor and cognitive defects | ||
| 2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID phenotype | |||||
| Common variable immune deficiency with no gene defect specified (CVID) | Unknown | Variable | NA | Low IgG and IgA and/or IgM | Clinical phenotypes vary most have recurrent infections; some have polyclonal lymphoproliferation, autoimmune cytopenias, and/or granulomatous disease |
| Activated p110δ syndrome (APDS) | PIK3CD GOF | AD | 615513 (APDS1) | Normal/increased IgM, reduced IgG and IgA | Severe bacterial infections, reduced memory B cells, and increased transitional B cells, EBV ± CMV viremia, lymphadenopathy/splenomegaly, autoimmunity, lymphoproliferation, lymphoma |
| PIK3R1 | AD | 616005 (APDS2) | Severe bacterial infections, reduced memory B cells, and increased transitional B cells, lymphadenopathy/splenomegaly, lymphoproliferation, lymphoma; developmental delay | ||
| PTEN deficiency (LOF) | PTEN | AD | 158350 | Normal/decreased | Recurrent infections, lymphoproliferation, autoimmunity; developmental delay |
| CD19 deficiency | CD19 | AR | 107265 | Low IgG and IgA and/or IgM | Recurrent infections, may have glomerulonephritis (CD81 mutation abolishes the expression of CD19, thereby phenocopying CD19 mutations) |
| CD81 deficiency | CD81 | AR | 186845 | Low IgG, low or normal IgA and IgM | |
| CD20 deficiency | MS4A1(CD20) | AR | 112210 | Low IgG, normal or elevated IgM and IgA | Recurrent infections |
| CD21 deficiency | CR2 (CD21) | AR | 120650 | Low IgG, impaired anti-pneumococcal response | Recurrent infections |
| TACI deficiency a | TNFRSF13B | AR or AD | 604907 | Low IgG and IgA and/or IgM | Variable clinical expression and penetrance for monoallelic variants |
| BAFF receptor deficiency | TNFRSF13C | AR | 606269 | Low IgG and IgM | Variable clinical expression |
| TWEAK deficiency | TNFSF12 | AD | 602695 | Low IgM and IgA, lack of anti-pneumococcal antibody | Pneumonia, bacterial infections, warts, thrombocytopenia, neutropenia |
| TRNT1 deficiency | TRNT1 | AR | 612907 | B-cell deficiency and hypogammaglobulinemia | Congenital sideroblastic anemia, deafness, developmental delay |
| NFKB1 deficiency | NFKB1 | AD | 164011 | Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells | Recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia, and autoimmune thyroiditis |
| NFKB2 deficiency | NFKB2 | AD | 615577 | Low serum IgG, IgA, and IgM; low B-cell numbers | Recurrent sinopulmonary infections, alopecia, and endocrinopathies |
| IKAROS deficiency | IKZF1 | AD (haploinsufficiency) | 603023 | Low IgG, IgA, IgM, low or normal B cells; B cells and Ig levels reduce with age | Decreased pro-B cells, recurrent sinopulmonary infections; increased risk of ALL, autoimmunity, CVID phenotype |
| IRF2BP2 deficiency | IRF2BP2 | AD | 615332 | Hypogammaglobulinemia, absent IgA | Recurrent infections, possible autoimmunity and inflammatory disease |
| ATP6AP1 deficiency | ATP6AP1 | XL | 300972 | Variable immunoglobulin findings | Hepatopathy, leukopenia, low copper |
| ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis |
| SH3KBP1 (CIN85) deficiency | SH3KBP1 | XL | 300310 | IgM, IgG deficiency; loss of antibody | Severe bacterial infections |
| SEC61A1 deficiency | SEC61A1 | AD | 609213 | Hypogammaglobulinemia | Severe recurrent respiratory tract infections |
| RAC2 deficiency | RAC2 | AR | 602049 | Low IgG, IgA, IgM, low or normal B cells; reduced Ab responses following vaccination | Recurrent sinopulmonary infections, selective IgA deficiency; poststreptococcal glomerulonephritis; urticaria |
| Mannosyl-oligosaccharide glucosidase deficiency | MOGS | AR | 601336 | Low IgG, IgA, IgM, increased B cells; poor Ab responses following vaccination | Bacterial and viral infections; severe neurological disease; also known as congenital disorder of glycosylation type IIb (CDG-IIb) |
| PIK3CG deficiency | PIK3CG | AR | 619802 | Reduced memory B cells, hypogammaglobulinemia | Recurrent infections, cytopenia/lymphopenia, eosinophilia, splenomegaly, lymphadenopathy, HLH-like |
| BOB1 deficiency | POU2AF1 | AR | NA | Reduced memory B cells, agammaglobulinemia | Recurrent respiratory infections, possible chronic viral infection of CNS with progressive tetraparesis |
| KARS1 deficiency | KARS1 | AR | 619147 | Impaired B-cell metabolism (decreased mitochondrial numbers and activity). B-cell lymphopenia, hypogammaglobulinemia, impaired vaccine responses | Severe developmental delay, sensorineural deafness, acute disseminated encephalomyelitis, central and peripheral nervous system impairment, heart and liver disease. Recurrent/severe infections |
| PI4KA deficiency | PI4KA | AR | 619708 | Reduced total B cells, few memory B cells, hypogammaglobulinemia | Recurrent infections; autoimmune/autoinflammatory, neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus with polymicrogyria, cerebellar hypoplasia, arthrogryposis), and gastrointestinal (inflammatory bowel disease, multiple intestinal atresia) manifestations |
| 3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper-IgM | |||||
| AID deficiency | AICDA | AR | 605258 | IgG and IgA decreased, IgM increased; normal memory B cells but lacking somatic hypermutation | Bacterial infections, enlarged lymph nodes and germinal centers; autoimmunity |
| AD | NA | IgG absent or decreased, IgA undetected, IgM increased; normal memory B cells with intact somatic hypermutation | Bacterial infections, enlarged lymph nodes and germinal centers. Variants uniquely localize to the nuclear export signal | ||
| UNG deficiency | UNG | AR | 191525 | IgG and IgA decreased, IgM increased | Enlarged lymph nodes and germinal centers |
| INO80 deficiency | INO80 | AR | 610169 | IgG and IgA decreased, IgM increased | Severe bacterial infections |
| MSH6 deficiency | MSH6 | AR | 600678 | Variable IgG, defects, increased IgM in some, normal B cells, low switched memory B cells, Ig class switch recombination and somatic hypermutation defects | Family or personal history of cancer |
| CTNNBL1 deficiency | CTNNBL1 | AR | 619846 | Reduced memory B cells, Ig class switch recombination and somatic hypermutation defects, progressive hypogammaglobulinemia | CVID, autoimmune cytopenias, recurrent infections, hyperplastic germinal centers |
| APRIL deficiency | TNFSF13 | AR | NA | Normal total B-cell counts, reduced memory B cells, hypogammaglobulinemia | CVID, chronic but mild infections, alopecia areata |
| 4. Isotype, light chain, or functional deficiencies with generally normal numbers of B cells | |||||
| Ig heavy chain mutations and deletions | Mutation or chromosomal deletion at 14q32 | AR | One or more IgG and/or IgA subclasses, as well as IgE, may be absent | May be asymptomatic | |
| Kappa chain deficiency | IGKC | AR | 147200 | All immunoglobulins have lambda light chain | Asymptomatic |
| Isolated IgG subclass deficiency | Unknown | ND | Reduction in one or more IgG subclass | Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections | |
| IgG subclass deficiency with IgA deficiency | Unknown | ND | Reduced IgA with a decrease in one or more IgG subclass | Recurrent bacterial infections May be asymptomatic | |
| Selective IgA deficiency | Unknown | ND | Absent IgA with other isotypes normal, normal subclasses, and specific antibodies | May be asymptomatic Bacterial infections, autoimmunity mildly increased | |
| Specific antibody deficiency with normal Ig levels and normal B cells | Unknown | ND | Normal | Reduced ability to produce antibodies to specific antigens | |
| Transient hypogammaglobulinemia of infancy | Unknown | ND | IgG and IgA decreased | Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections | |
| CARD11 GOF | CARD11 | AD GOF | 616452 | Polyclonal B-cell lymphocytosis due to constitutive NF-κB activation | Splenomegaly, lymphadenopathy, poor vaccine response |
| Selective IgM deficiency | Unknown | ND | Absent serum IgM | Pneumococcal/bacterial | |
Footnotes:
EBV, Epstein-Barr virus; COPD, chronic obstructive pulmonary disease; ND, not determined; CNS, central nervous system; VODI, hepatic veno-occlusive disease with immunodeficiency; IBD, inflammatory bowel disease; CVID, common variable immunodeficiency; Ab, antibody.
CVID disorders include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells, as well as hypogammaglobulinemia. Identification of causal variants can assist in defining treatment. In addition to monogenic causes on this table, a small minority of patients with XLP ( Table 4 ), WHIM syndrome ( Table 6 ), ICF ( Table 2 ), VODI ( Table 2 ), thymoma with immunodeficiency (Good syndrome), or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia, and normal or reduced numbers of B cells.
Total number of mutant genes in Table 3 : 48.
New IEIs: 3, PAX5 , KARS1 , and PI4K4 ( 48 , 49 , 50 ).
Heterozygous variants in TNFRSF13B have been detected in healthy individuals; thus, such variants are likely to be disease-modifying rather than disease-causing.
Table 4. Diseases of immune dysregulation
| Disease | Genetic defect | Inheritance | OMIM | Circulating T cells | Circulating B cells | Functional defect | Associated 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 | |
Footnotes:
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.
Table 5. Congenital defects of phagocyte number or function
| Disease | Genetic defect | Inheritance | OMIM | Affected cells | Affected function | Associated features |
|---|---|---|---|---|---|---|
| 1. Congenital neutropenias | ||||||
| Elastase deficiency (severe congenital neutropenia [SCN] 1) | ELANE | AD | 130130 | N | Myeloid differentiation | Susceptibility to MDS/leukemia Severe congenital neutropenia or cyclic neutropenia |
| GFI 1 deficiency (SCN2) | GFI1 | AD | 600871 | N | Myeloid differentiation | B/T lymphopenia |
| HAX1 deficiency (Kostmann disease) (SCN3) | HAX1 | AR | 605998 | N | Myeloid differentiation | Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia |
| G6PC3 deficiency (SCN4) | G6PC3 | AR | 611045 | N | Myeloid differentiation, chemotaxis O2− production | Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasia of trunks and limbs |
| VPS45 deficiency (SCN5) | VPS45 | AR | 610035 | N | Myeloid differentiation, migration | Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly |
| Glycogen storage disease type 1b | SLC37A4/G6PT1 | AR | 602671 | N + M | Myeloid differentiation, chemotaxis, O2− production | Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly |
| X-linked neutropenia/myelodysplasia | WAS | XL GOF | 300299 | N | Differentiation, mitosis. Results from GOF mutations in GTPase binding domain of WASP | Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies |
| P14/LAMTOR2 deficiency | LAMTOR2 | AR | 610389 | N + M | Endosomal biogenesis | Neutropenia Hypogammaglobulinemia CD8− cytotoxicity, partial albinism, growth failure |
| Barth syndrome (3-methylglutaconic aciduria type II) | TAZ | XL | 300394 | N+L Mel | Mitochondrial function | Cardiomyopathy, myopathy, growth retardation, neutropenia |
| Cohen syndrome | VPS13B | AR | 607817 | N | Myeloid differentiation | Dysmorphism, mental retardation, obesity, deafness, neutropenia |
| Clericuzio syndrome (poikiloderma with neutropenia) | USB1 | AR | 613276 | N | Myeloid differentiation | Retinopathy, developmental delay, facial dysmorphisms, poikiloderma |
| JAGN1 deficiency | JAGN1 | AR | 616012 | N | Myeloid differentiation | Myeloid maturation arrest, osteopenia |
| 3-Methylglutaconic aciduria | CLPB | AD/AR | 616254 | N | Myeloid differentiation Mitochondrial protein | Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR |
| G-CSF receptor deficiency | CSF3R | AR | 138971 | N | Stress granulopoiesis disturbed | |
| SMARCD2 deficiency | SMARCD2 | AR | 601736 | N | Chromatin remodeling, myeloid differentiation, and neutrophil functional defect | Neutropenia, developmental aberrations, bones, hematopoietic stem cells, myelodysplasia |
| CEBPE deficiency | CEBPE | AR | 245480 | N | Terminal maturation and global dysfunction | Neutropenia, neutrophils with bilobed nuclei, poor chemotaxis |
| Shwachman–Diamond syndrome | SBDS | AR | 607444 | N | Neutrophil maturation, chemotaxis, ribosomal biogenesis | Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia |
| DNAJC21 | AR | 617052 | N + HSC | Pancytopenia, exocrine pancreatic insufficiency | ||
| EFL1 | AR | 617941 | N + HSC | |||
| HYOU1 deficiency | HYOU1 | AR | 601746 | N | Unfolded protein response | Hypoglycemia, inflammatory complications |
| SRP54 deficiency | SRP54 | AD | 604857 | N | Protein translocation to ER, myeloid differentiation, and neutrophil functional defect | Neutropenia, exocrine pancreatic insufficiency |
| CXCR2 deficiency | CXCR2 | AR | 619407 | N | Reduced expression of CXCR2 on patient cells, impaired responses to CXCL8 | Profound neutropenia, myelokathexis, recurrent gingivitis, oral ulcers, hypergammaglobulinemia |
| DBF4 deficiency | DBF4 | AR | NA | N | Disturbed cell cycle | Neurocognitive developmental aberrations |
| SRP19/SRPRA deficiency | SRP19 | AR | NA | N | Alterations in neutrophil granulocyte development with reduction in electron-dense granules | Exocrine pancreatic insufficiency, growth insufficiency, recurrent pulmonary infections with bronchiectasis, congenital neutropenia |
| SRPRA | ||||||
| 2. Defects of motility | ||||||
| Leukocyte adhesion deficiency type 1 (LAD1) | ITGB2 | AR | 600065 | N + M + L + NK | Adherence, chemotaxis, endocytosis, T/NK cytotoxicity | Delayed cord separation, skin ulcers, periodontitis, leukocytosis |
| Leukocyte adhesion deficiency type 2 (LAD2) | SLC35C1 | AR | 605881 | N + M | Rolling, chemotaxis | Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay |
| Leukocyte adhesion deficiency type 3 (LAD3) | FERMT3 | AR | 607901 | N + M + L + NK | Adherence, chemotaxis | LAD type 1 plus bleeding tendency |
| Rac2 deficiency | RAC2 | AD LOF | 608203 | N | Adherence, chemotaxis O2− production | Poor wound healing, leukocytosis |
| β-Actin deficiency | ACTB | AD | 102630 | N + M | Motility | Mental retardation, short stature |
| Localized juvenile periodontitis | FPR1 | AR | 136537 | N | Formyl peptide–induced chemotaxis | Periodontitis only |
| Papillon–Lefèvre syndrome | CTSC | AR | 602365 | N + M | Chemotaxis | Periodontitis, palmoplantar hyperkeratosis in some patients |
| WDR1 deficiency | WDR1 | AR | 604734 | N | Spreading, survival, chemotaxis | Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nucleus herniate |
| Cystic fibrosis | CFTR | AR | 602421 | M only | Chemotaxis | Respiratory infections, pancreatic insufficiency, elevated sweat chloride |
| Neutropenia with combined immune deficiency due to MKL1 deficiency | MAP3K9/MKL1 | AR | 606078 | N + M +L + NK | Impaired expression of cytoskeletal genes | Mild thrombocytopenia |
| CCR2 | CCR2 | AR | 219600 | M | Impaired CCL2-dependent monocyte migration to the lungs and infected tissues | Pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including BCG disease |
| 3. Defects of respiratory burst | ||||||
| X-linked chronic granulomatous disease (CGD), gp91phox | CYBB | XL | 306400 | N + M | Killing (faulty O2− production) | Infections, autoinflammatory phenotype, IBD McLeod phenotype in patients with deletions extending into the contiguous Kell locus |
| AR CGD | CYBA | AR | 608508 | Infections, autoinflammatory phenotype | ||
| CYBC1 | 618334 | |||||
| NCF1 | 608512 | |||||
| NCF2 | 608515 | |||||
| NCF4 | 613960 | |||||
| G6PD deficiency class I | G6PD | XL | 305900 | N | Reduced O2− production | Infections |
| 4. Other nonlymphoid defects | ||||||
| Pulmonary alveolar proteinosis | CSF2RA | XL (biallelic mutations in pseudoautosomal gene) | 300770 | Alveolar macrophages | GM-CSF signaling | Alveolar proteinosis |
| CSF2RB | AR | 614370 | ||||
Footnotes:
MDS, myelodysplastic syndrome; IUGR, intrauterine growth retardation; LAD, leukocyte adhesion deficiency; AML, acute myelogenous leukemia; N, neutrophil; M, monocyte; MEL, melanocyte; L, lymphocyte; NK, natural killer; BCG, bacillus Calmette–Guérin; IBD, inflammatory bowel disease.
Total number of defects in Table 5 : 45.
New IEIs: 4, DBF4 , SRP19 , SRPRA , and CCR2 ( 73 , 74 , 75 ).
Table 6. Defects in intrinsic and innate immunity
| Disease | Genetic defect | Inheritance | OMIM | Affected cells | Affected function | Associated features |
|---|---|---|---|---|---|---|
| 1. Mendelian susceptibility to mycobacterial disease (MSMD) | ||||||
| IL-12 and IL-23 receptor β1 chain deficiency | IL12RB1 | AR | 601604 | L + NK+MAIT | IFN-γ secretion | Susceptibility to mycobacteria and Salmonella and CMC |
| IL-12p40 (IL-12 and IL-23) deficiency | IL12B | AR | 161561 | M | ||
| IL-12Rβ2 deficiency | IL12RB2 | AR | 601642 | L + NK+MAIT | ||
| IL-23R deficiency | IL23R | AR | 607562 | L +NK+MAIT | ||
| IFN-γ receptor deficiency | IFNGR1 | AR | 209950 | M + L | IFN-γ binding and signaling | |
| AD | 615978 | M + L | ||||
| IFNGR2 | AR | 147569 | M + L | IFN-γ signaling | ||
| STAT1 deficiency | STAT1 | AD LOF | 614892 | M + L | ||
| Macrophage gp91phox deficiency Q231P and T178P | CYBB | XL | 300645 | Macrophage only | Respiratory burst defect in monocytes (not in neutrophils) | Isolated susceptibility to mycobacteria |
| IRF8 deficiency | IRF8 | AD | 614893 | M + L | Impaired development of cDCs and Th1* cells | Susceptibility to mycobacteria |
| AR | 226990 | M | Lack of circulating monocytes and DCs, reduced NK cell numbers and function reported in some patients | Susceptibility to mycobacteria and multiple other infectious agents including EBV | ||
| SPPL2a deficiency | SPPL2A | AR | 608238 | M + L | Impaired development of cDCs and Th1* cells | Susceptibility to mycobacteria and Salmonella |
| TYK2 deficiency | TYK2 | AR | 611521 | M + L | Impaired cellular responses to IL-10, IL-12, IL-23, and type I IFNs | Susceptibility to intracellular bacteria (mycobacteria, Salmonella) and viruses |
| P1104A TYK2 homozygosity | AR | 176941 | L | Impaired cellular responses to IL-23 | MSMD or tuberculosis | |
| ISG15 deficiency | ISG15 | AR | 147571 | IFN-γ production defect | Susceptibility to mycobacteria (BCG), brain calcification | |
| RORγt deficiency | RORC | AR | 602943 | L + NK | Lack of functional RORγT protein, IFN-γ production defect, complete absence of IL-17A/F–producing T cells | Susceptibility to mycobacteria and candida |
| JAK1 deficiency | JAK1 | AR LOF | 147795 | N + L | Reduced JAK1 activation to cytokines Reduced IFN-γ production | Susceptibility to mycobacteria and viruses, urothelial carcinoma |
| T-bet deficiency | TBX21 | AR | 619630 | L | ↓IFN-γ and TNF-α production by γδT cells, MAIT cells, iNKT cells, NK cells, and CD4+ T cells | Susceptibility to mycobacteria |
| IFN-γ deficiency | IFNG | AR | 618963 | L | No IFN-γ production by patient T and NK cells | Susceptibility to mycobacteria |
| IRF1 deficiency | IRF1 | AR | 620668 | Lymphocytes, DCs, NK, ILCP, ILCP2 | IRF1-dependent responses to IFN-γ are both quantitatively and qualitatively stronger than those to IFN-α/β. IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ, while IFN-α/β–dependent intrinsic immunity to viruses seems unaffected | Early-onset severe forms of MSMD due to BCG,M. avium complex. No history of severe viral illnesses. Histoplasmosis in 2 patients |
| MCTS1 deficiency | MCTS1 | XLR | 301115 | Lymphocytes | Impaired cellular responses to IL-23 and partially IL-12, impaired IL-23dep IFN-γ induction by MAIT and γδT cells | Life-threatening early-onset BCG disease. Disease was multifocal or disseminated in several cases including osteomyelitis |
| 2. Epidermodysplasia verruciformis (HPV) | ||||||
| EVER1 deficiency | TMC6 | AR | 605828 | Keratinocytes | EVER1, EVER2, and CIB1 form a complex in keratinocytes | HPV (group B1) infections and cancer of the skin (typical EV) |
| EVER2 deficiency | TMC8 | 605829 | ||||
| CIB1 deficiency | CIB1 | 618267 | ||||
| WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome | CXCR4 | AD GOF | 162643 | Leukocytes | Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) | Warts (HPV) infection, neutropenia, low B-cell number, hypogammaglobulinemia |
| 3. Predisposition to severe viral infection | ||||||
| STAT1 deficiency | STAT1 | AR LOF | 600555 | Leukocytes and other cells | STAT1-dependent IFN-α/β, INF-γ, and IFN-λ responses | Severe viral infections, mycobacterial infection |
| STAT2 deficiency | STAT2 | AR | 600556 | Leukocytes and other cells | STAT2-dependent IFN-α/β, IFN-γ, and IFN-λ responses | Severe viral infections (disseminated vaccine-strain measles), influenza, HSV, enterovirus; atypical Kawasaki disease, HLH |
| IRF9 deficiency | IRF9 | AR | 618648 | Leukocytes and other cells | IRF9- and ISGF3-dependent IFN-α/β and IFN-λ responses | Severe influenza disease |
| IRF7 deficiency | IRF7 | AR | 605047 | Leukocytes, plasmacytoid DCs, nonhematopoietic cells | IFN-α, IFN-β, and IFN-γ production and IFN-l production | |
| IFNAR1 deficiency | IFNAR1 | AR | 619935 | Leukocytes and other cells | IFNAR1-dependent responses to IFN-α/β | Severe viral infections (dissemination of yellow fever vaccine and measles vaccine) |
| IFNAR2 deficiency | IFNAR2 | AR | 602376 | Broadly expressed | IFNAR2-dependent responses to IFN-α/β | Severe viral infections (disseminated vaccine-strain measles, HHV6) |
| CD16 deficiency | FCGR3A | AR | 146740 | NK cells | Altered NK cell function | Severe herpes viral infections, particularly VZV,EBV, and HPV |
| MDA5 deficiency | IFIH1 | AR LOF | 606951 | Broadly expressed | Viral recognition and IFN induction | Rhinovirus and other RNA viruses |
| NOS2 deficiency | NOS2 | AR | NA | Myeloid cells | Mutant NOS2 failed to induce nitrous oxide | Severe (fatal) susceptibility to CMV-induced disease; pneumocystis pneumonia secondary to CMV; intact responses to infection with other herpesviruses (EBV, VZV, HSV) |
| ZNFX1 deficiency | ZNFX1 | AR | 619644 | Broadly expressed | ↑ ISG in response to poly I/C | Severe infections by RNA/DNA viruses, mycobacteria; early-onset severe inflammation affecting liver, brain, kidneys, lungs; virally triggered inflammatory episodes, hepatosplenomegaly, lymphadenopathy |
| RNA polymerase III deficiency | POLR3A | AD | 614258 | Leukocytes and other cells | Impaired viral recognition and IFN induction in response to VZV or poly I:C | Severe VZV infection |
| POLR3C | AD | 617454 | ||||
| POLR3F | AD | 617455 | ||||
| MIS-C | OAS1 | AR | Monocytic phagocytes | Excessive inflammatory cytokine production by monocytes | Multisystemic inflammatory syndrome in children (MIS-C) after SARS-CoV-2 | |
| OAS2 | AR | Monocytic phagocytes | Excessive inflammatory cytokine production by monocytes | MIS-C | ||
| RNASEL | AR | Monocytic phagocytes | Excessive inflammatory cytokine production by monocytes | MIS-C | ||
| 4. Herpes simplex encephalitis (HSE) | ||||||
| TLR3 deficiency | TLR3 | AD | 613002 | CNS-resident cells and fibroblasts | TLR3-dependent IFN-α, IFN-β, and IFN-γ response | Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here); severe pulmonary influenza; VZV |
| AR | ||||||
| UNC93B1 deficiency | UNC93B1 | AR | 608204 | UNC-93B–dependent IFN-α, IFN-β, and IFN-γ response | Herpes simplex virus 1 encephalitis | |
| TRAF3 deficiency | TRAF3 | AD | 601896 | TRAF3-dependent IFN-α, IFN-β, and IFN-γ response | ||
| TRIF deficiency | TICAM1 | AD | 607601 | TRIF-dependent IFN-α, IFN-β, and IFN-γ response | ||
| AR | ||||||
| TBK1 deficiency | TBK1 | AD | 604834 | TBK1-dependent IFN-α, IFN-β, and IFN-γ response | ||
| IRF3 deficiency | IRF3 | AD | 616532 | Low IFN-α/β, production in response to HSV1 and decreased IRF3 phosphorylation | ||
| DBR1 deficiency | DBR1 | AR | 607024 | Impaired production of antiviral IFNs | HSE of the brainstem. Other viral infections of the brainstem | |
| SNORA31 deficiency | SNORA31 | AD | 619396 | Impaired production of antiviral IFNs | Forebrain HSV1 encephalitis | |
| ATG4A deficiency | ATG4 | AD | NA | CNS-resident cells and fibroblasts | Impaired HSV2-induced autophagy →increased viral replication and apoptosis of patient fibroblasts | Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2 |
| MAP1LC3B2 deficiency | MAP1LC3B2 | |||||
| RIPK3 deficiency | RIPK3 | AR | NA | Neurons | Impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection | Herpes simplex encephalitis recurrent in one patient. Otherwise, healthy |
| GTF3A deficiency | GTF3A | AR | NA | Fibroblasts | ↓ RNA5SP141 expression results in abrogated RIG-I activation upon HSV-1 infection | CVID phenotype, low switched memory B cells, absent IgM. Defect in pneumococcal antibody response. T cells, mostly memory effector phenotype, low TFH and TH17 cells |
| IKBKE deficiency | IKBKE | AD | NA | Microglia | Impaired induction of IFN-β1 (IFNB1) upon HSV-2 infection or dsDNA stimulation. Failure to induce phosphorylation of STING | Recurrent HSV-2 meningitis |
| 5. Predisposition to invasive fungal diseases | ||||||
| CARD9 deficiency | CARD9 | AR | 607212 | Mononuclear phagocytes | CARD9 signaling pathway | Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections |
| 6. Predisposition to mucocutaneous candidiasis | ||||||
| IL-17RA deficiency | IL17RA | AR | 605461 | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RA signaling pathway, and fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E | CMC, folliculitis |
| IL-17RC deficiency | IL17RC | AR | 610925 | IL-17RC signaling pathway, fibroblasts fail to respond to IL-17A and IL-17F | CMC | |
| IL-17F deficiency | IL17F | AD | 606496 | T cells | IL-17F–containing dimers | CMC |
| STAT1 GOF | STAT1 | AD GOF | 600555 | T cells, B cells, NK, monocytes | Increased STAT1 phosphorylation Low Th17 cells | CMC, various fungal, bacterial, and viral (HSV) infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy |
| ACT1 deficiency | TRAF3IP2 | AR | 607043 | T cells, fibroblasts | Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E | CMC, blepharitis, folliculitis, and macroglossia |
| JNK1 haploinsufficiency | MAPK8 | AD | NA | T cells, fibroblasts | ↓ Th17 cells ex vivo, in vitro, ↓ responses of fibroblasts to IL-17A, IL-17F, ↓ c-Jun/ATF-2-dependent TGF-β signaling | CMC, connective tissue disorder (similar to Ehlers–Danlos syndrome) |
| 7. TLR signaling pathway deficiency | ||||||
| IRAK4 deficiency | IRAK4 | AR | 606883 | Lymphocytes + granulocytes + monocytes | TIR-IRAK4 signaling pathway | Pyogenic bacterial diseases, severe viral diseases |
| MyD88 deficiency | MYD88 | AR | 602170 | Lymphocytes + granulocytes + monocytes | TIR-MyD88 signaling pathway | |
| Systemic autoinflammation splenomegaly and anemia (NASA) | IRAK4 | AR | 607676 | Lymphocytes | Loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production | Recurrent episodes of fever, massive splenomegaly, elevated inflammatory markers, and severe hypochromic microcytic anemia |
| IRAK1 deficiency | IRAK1 | XL | 300283 | Lymphocytes + granulocytes + monocytes | TLR-IRAK1 signaling pathway in fibroblasts, TLR7- and TLR8-IRAK1 signaling pathway in EBV-B cells | Bacterial infections, X-linked MECP2 deficiency–related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 |
| TIRAP deficiency | TIRAP | AR | 614382 | Lymphocytes + granulocytes + monocytes | TIRAP signaling pathway, TLR1/2, TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes | Staphylococcal disease during childhood in the patient lacking lipoteichoic acid Abs |
| TLR7 deficiency | TLR7 | XL | 301051 | Lymphocytes, myeloid cells | Impaired responses to TLR7 ligands; reduced production of type 1 IFN | Severe COVID-19 infection |
| TLR8 GOF | TLR8 | XL/somatic mutations | 301078 | Myeloid cells | Elevated proinflammatory serum cytokines; increased proinflammatory responses of patient myeloid cells to TLR8 agonists; reduced ability of mutant TLR8 to attenuate TLR7 signaling | Early-onset, severe cytopenias, hepatosplenomegaly, lymphadenopathy; progressive autoinflammatory disease |
| MD2 deficiency | LY96 | AR | NA | Myeloid cells | Decreased endocytosis of TLR4 leads to impaired NF-κB signaling and decreased cytokine production | Very early-onset inflammatory bowel disease and recurrent infections, pneumonia, and otitis media |
| TLR4 deficiency | TLR4 | AR | NA | Impaired TLR4 signaling | Inflammatory bowel disease | |
| 8. Other IEIs related to nonhematopoietic tissues | ||||||
| Isolated congenital asplenia (ICA) | RPSA | AD | 271400 | No spleen | RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome | Bacteremia (encapsulated bacteria) |
| HMOX | AR | 141250 | Macrophages | HO-1 regulates iron recycling, and heme-dependent damage occurs | Hemolysis, nephritis, inflammation | |
| Trypanosomiasis | APOL1 | AD | 603743 | Somatic | Pore-forming serum protein | Trypanosomiasis |
| Acute liver failure due to NBAS deficiency | NBAS | AR | 608025 | Somatic and hematopoietic | ER stress | Fever induces liver failure |
| Acute necrotizing encephalopathy | RANBP2 | AD | 601181 | Ubiquitous expression | Nuclear pore | Fever induces acute encephalopathy |
| Osteopetrosis | CLCN7 | AR/AD | 602727 | Osteoclasts | Secretory lysosomes | Osteopetrosis with hypocalcemia, neurological features |
| SNX10 | AR | 614780 | Osteopetrosis with visual impairment | |||
| OSTM1 | AR | 607649 | Osteopetrosis with hypocalcemia, neurological features | |||
| PLEKHM1 | AR | 611466 | Osteopetrosis | |||
| TCIRG1 | AR | 604592 | Osteopetrosis with hypocalcemia | |||
| TNFRSF11A | AR | 603499 | Osteoclastogenesis | Osteopetrosis | ||
| TNFSF11 | AR | 602642 | Stromal | Osteoclastogenesis | Osteopetrosis with severe growth retardation | |
| Hidradenitis suppurativa | NCSTN | AD | 605254 | Epidermis | Notch signaling/gamma-secretase in hair follicle regulates keratinization | Verneuil’s disease/hidradenitis suppurativa with acne |
| PSEN | AD | 613737 | Verneuil’s disease/hidradenitis suppurativa with cutaneous hyperpigmentation | |||
| PSENEN | AD | 613736 | Verneuil’s disease/hidradenitis suppurativa | |||
| 9. Other IEIs related to leukocytes | ||||||
| IRF4 haploinsufficiency | IRF4 | AD | 601900 | Lymphocytes and monocytes | IRF4 is a pleiotropic transcription factor | Whipple’s disease |
| IL-18BP deficiency | IL18BP | AR | 604113 | Leukocytes and other cells | IL-18BP neutralizes secreted IL-18 | Fulminant viral hepatitis |
| GATA2 deficiency | GATA2 | AD | 137295 | Monocytes + peripheral DC, NK cells | Multilineage cytopenia | Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMML, lymphedema |
Footnotes:
NF-κB, nuclear factor kappa B; TIR, Toll and interleukin-1 receptor; IFN, interferon; TLR, Toll-like receptor; MDC, myeloid dendritic cell; CNS, central nervous system; CMC, chronic mucocutaneous candidiasis; HPV, human papillomavirus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; CVID, common variable immunodeficiency; Abs, antibodies.
Total number of mutant genes in Table 6 : 86 diseases with 2 entries for IRAK4 counted separately as they constitute different genetic mechanisms and associated phenotypes. GATA2 was moved from nonlymphoid disease table to Table 6 , subtable 9.
New IEIs: 10, IRF1 , MCTS1 , OAS1 , OAS2 , RNASEL , RIPK3 , MD2 , TLR4 , GTF3A , and IKBKE ( 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ).
* after Th1 refers to Th1 cells, which are a specificsubset of human CD4+ T cells and are specifically affected by the indicatedgene mutations i.e. IRF8, SPPL2A.
Table 7. Autoinflammatory disorders
| Disease | Genetic defect | Inheritance | OMIM | T cells | B cells | Functional defect | Associated features |
|---|---|---|---|---|---|---|---|
| 1. Type 1 interferonopathies | |||||||
| AD STING-associated vasculopathy, infantile-onset (SAVI) | TMEM173** (STING) | AD | 612374 | Not assessed | Not assessed | STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN | Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL |
| AR STING-associated vasculopathy, infantile-onset (SAVI) | AR GOF | 615934 | Not assessed | Not assessed | STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN | FTT, early-onset rash, fever, dyspnea, interstitial lung disease/pneumonitis, polyarthritis, autoAbs, increased inflammatory markers, IFN gene signature. Phenocopy of SAVI due to AD GOF TMEM173 | |
| ADA2 deficiency | ADA2 | AR | 607575 | Not assessed | Not assessed | ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors | Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; some patients develop hypogammaglobulinemia |
| TREX1 deficiency, Aicardi–Goutières syndrome 1 (AGS1) | TREX1 | AR | 606609 | Not assessed | Not assessed | Intracellular accumulation of abnormal ssDNA species leading to increased type I IFN production | Classical AGS, SLE, FCL |
| AD | |||||||
| RNASEH2B deficiency, AGS2 | RNASEH2B | AR | 610326 | Not assessed | Not assessed | Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production | Classical AGS, SP |
| RNASEH2C deficiency, AGS3 | RNASEH2C | AR | 610330 | Not assessed | Not assessed | Classical AGS | |
| RNASEH2A deficiency, AGS4 | RNASEH2A | AR | 606034 | Not assessed | Not assessed | Classical AGS | |
| SAMHD1 deficiency, AGS5 | SAMHD1 | AR | 606754 | Not assessed | Not assessed | Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production | Classical AGS, FCL |
| ADAR1 deficiency, AGS6 | ADAR1 | AR | 615010 | Not assessed | Not assessed | Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production | Classical AGS, BSN, SP |
| AD (G1007R) | NA | ||||||
| Aicardi–Goutières syndrome 7 (AGS7) | IFIH1 | AD GOF | 615846 | Not assessed | Not assessed | IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule | Classical AGS, SLE, SP, SMS |
| DNase II deficiency | DNASE2 | AR | 619858 | Not assessed | Not assessed | DNase II degrades and eliminates DNA. Loss of DNase II activity induces type I interferon signaling | AGS |
| LSM11 deficiency | LSM11 | AR | 619486 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| RNU7-1 deficiency | RNU7-1 | AR | 619487 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| ARF1 deficiency | ARF1 | AD | 103180 | Not assessed | Not assessed | Increased type I IFN signaling in cell lines and patient cells | AGS, type 1 IFN-opathy |
| Pediatric SLE due to DNASE1L3 deficiency | DNASE1L3 | AR | 614420 | DNASE1L3 is an endonuclease that degrades extracellular DNA. DNASE1L3 deficiency decreases clearance of apoptotic cells | Very early-onset SLE, reduced complement levels, autoantibodies (dsDNA, ANCA), lupus nephritis, hypocomplementemic urticarial vasculitis syndrome | ||
| Spondyloenchondrodysplasia with immune dysregulation (SPENCD) | ACP5 | AR | 171640 | Not assessed | Not assessed | Upregulation of IFN through mechanism possibly relating to pDCS | Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections |
| USP18 deficiency | USP18 | AR | 607057 | Not assessed | Not assessed | Defective negative regulation of ISG15 leading to increased IFN | TORCH-like syndrome, autoinflammation, and mycobacterial disease |
| OAS1 GOF | OAS1 | AD GOF | 618042 | Low | Increased interferon from recognition of RNA | Pulmonary alveolar proteinosis, skin rash | |
| CDC42 deficiency | CDC42 | AD | 616737 | Normal/decreased | Normal/decreased | ↑serum levels of IL-1, IL-18, IFN-α↑, ferritin, sCD25, CRP, etc. Mutation affects actin function, ↓ NK cell cytotoxicity | Neonatal onset: pancytopenia, fever, rash, hepatosplenomegaly, multisystemic inflammation, myelofibrosis/proliferation, HLH, enterocolitis; recurrent GIT/URT infections; neurodevelopmental delay, FTT |
| STAT2 loss of negative regulation | STAT2 | AR | 616636 | Increased | Normal | Patient cells hypersensitive to IFN-α, GOF for induction of the late (not early) response to type 1 IFNs due to impaired interaction of mutant STAT2 with USP18, a negative regulator of type 1 IFN responses | Severe fatal early-onset autoinflammation, ↑serum IFN-α, IL-6, TNF-α, phenocopy of USP18 deficiency |
| ATAD3A deficiency | ATAD3A | AD/AR | 617183 | Not assessed | Not assessed | Elevated ISG expression, increased serum type 1 IFNs | Predominantly neurological defects (development delay, spasticity) |
| RELA haploinsufficiency | RELA | AD | 618287 | Normal/increased | Normal | Chronic mucocutaneous ulceration Impaired NF-κB activation; reduced production of inflammatory cytokines | |
| RELA interferonopathy a | RELA | AD DN | 618287 | Leukocyte TLR7-dependent type I/III IFN production | Patients with RELA DN mutations shared clinical phenotypes with RELA haploinsufficiency, presenting chronic mucocutaneous ulcerations and autoimmune hematological disorders such as immune thrombocytopenia (ITP) and neutropenia. However, patients with RELA DN mutations additionally presented periodic fever, IBD juvenile idiopathic arthritis (JIA), and skin involvement | ||
Footnotes:
IFN, interferon; HSM, hepatosplenomegaly; CSF, cerebrospinal fluid; SLE, systemic lupus erythematosus; TORCH, toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections; SNHL, sensorineural hearing loss; AGS, Aicardi-Goutières syndrome; BSN, bilateral striatal necrosis; FCL, familial chilblain lupus; ICC, intracranial calcification; IFN, interferon type I; pDCs, plasmacytoid dendritic cells; SP, spastic paraparesis; SMS, Singleton–Merten syndrome; ss, single-stranded; ADA, adenosine deaminase; CNS, central nervous system; IBD, inflammatory bowel disease; autoAbs, autoantibodies.
* variants in PSMB4 , PSMB9 , PSMA3 , and POMP have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic ( PSMB4 ), digenic ( PSMA3/PSMB8 , PSMB9/PSMB4 , PSMB4/PSMB8 ), and AD monogenic ( POMP ) models ( 119 ). Only G156D mutation in PSMB9 has been shown to cause an autoinflammatory phenotype with immunodeficiency in patients and mouse model ( 120 ).
Total number of disorders in Table 7 : 69.
New IEIs: 11, STAT4 GOF, PMVK , ALPK1 , LYN GOF, SHARPIN , LSM11 , RNU71 , ARF1 , OTULIN (two new entries), and RELA ( 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ).
** depicts that somatic mutations mimicking the germline disorder have been described for this gene.
RELA previously described as causing combined immunodeficiency a second entry included here as DN mutations are associated with an inflammatory phenotype with different mechanism of disease. OTULIN is repeated three times as different mechanisms of disease give rise to different phenotypes. NLRP1 is also repeated twice as AR and AD forms result in different phenotypes.
Table 8. Complement deficiencies
| Disease | Genetic defect | Inheritance | Gene OMIM | Laboratory features | Associated features |
|---|---|---|---|---|---|
| Complement deficiencies | |||||
| C1q deficiency due to defects | C1QA | AR | 120550 | Absent CH50 hemolytic activity, defective activation of the classical pathway, diminished clearance of apoptotic cells | SLE, infections with encapsulated organisms |
| C1QB | AR | 120570 | |||
| C1QC | AR | 120575 | |||
| C1r deficiency | C1R | AR | 613785 | Absent CH50 hemolytic activity, defective activation of the classical pathway | SLE, infections with encapsulated organisms, Ehlers–Danlos phenotype |
| C1r Periodontal Ehlers–Danlos | C1R | AD GOF | 613785 | Normal CH50 | Hyperpigmentation, skin fragility |
| C1s deficiency | C1S | AR | 613785 | Absent CH50 hemolytic activity, defective activation of the classical pathway | SLE, infections with encapsulated organisms, Ehlers–Danlos phenotype |
| C1s Periodontal Ehlers–Danlos | C1S | AD GOF | 613785 | Normal CH50 | Hyperpigmentation, skin fragility |
| Complete C4 deficiency | C4A+C4B | AR | 120810 | Absent CH50 hemolytic activity, defective activation of the classical pathway, complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B | SLE, infections with encapsulated organisms, partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense |
| C2 deficiency | C2 | AR | 217000 | Absent CH50 hemolytic activity, defective activation of the classical pathway | SLE, infections with encapsulated organisms, atherosclerosis |
| C3 deficiency (LOF) | C3 | AR | 120700 | Absent CH50 and AH50 hemolytic activity, defective opsonization, defective humoral immune response | Infections, glomerulonephritis, atypical hemolytic–uremic syndrome with GOF mutations |
| C3 GOF | C3 | AD GOF | 120700 | Increased activation of complement | Atypical hemolytic–uremic syndrome |
| C5 deficiency | C5 | AR | 120900 | Absent CH50 and AH50 hemolytic activity Defective bactericidal activity | Disseminated neisserial infections |
| C6 deficiency | C6 | AR | 217050 | Absent CH50 and AH50 hemolytic activity, defective bactericidal activity | |
| C7 deficiency | C7 | AR | 217070 | ||
| C8α deficiency | C8A | AR | 120950 | ||
| C8γ deficiency | C8G | AR | 120930 | ||
| C8β deficiency | C8B | AR | 120960 | ||
| C9 deficiency | C9 | AR | 120940 | Reduced CH50 and AP50 hemolytic activity, deficient bactericidal activity | Mild susceptibility to disseminated neisserial infections |
| MASP2 deficiency | MASP2 | AR | 605102 | Deficient activation of the lectin activation pathway | Pyogenic infections, inflammatory lung disease, autoimmunity |
| Ficolin-3 deficiency | FCN3 | AR | 604973 | Absence of complement activation by the ficolin-3 pathway | Respiratory infections, abscesses |
| C1 inhibitor deficiency | SERPING1 | AD/AR | 606860 | Spontaneous activation of the complement pathway with consumption of C4/C2, spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen | Hereditary angioedema |
| Factor B GOF | CFB | AD GOF | 612924 | GOF mutation with increased spontaneous AH50 | Atypical hemolytic–uremic syndrome |
| Factor B deficiency | CFB | AR | 615561 | Deficient activation of the alternative pathway | Infections with encapsulated organisms |
| Factor D deficiency | CFD | AR | 134350 | Absent AH50 hemolytic activity | Neisserial infections |
| Properdin deficiency | CFP | XL | 300383 | Absent AH50 hemolytic activity | Neisserial infections |
| Factor I deficiency | CFI | AR | 217030 | Spontaneous activation of the alternative complement pathway with consumption of C3 | Infections, disseminated neisserial infections, atypical hemolytic–uremic syndrome, preeclampsia |
| Factor H deficiency | CFH | AR or AD | 134370 | Spontaneous activation of the alternative complement pathway with consumption of C3 | |
| Factor H–related protein deficiencies | CFHR1 | AR or AD | 134371 | Normal CH50, AH50, autoantibodies to factor H, linked deletions of one or more CFHR genes lead to susceptibility to autoantibody-mediated aHUS | Older onset atypical hemolytic–uremic syndrome, disseminated neisserial infections |
| CFHR2 | 600889 | ||||
| CFHR3 | 605336 | ||||
| CFHR4 | 605337 | ||||
| CFHR5 | 608593 | ||||
| Thrombomodulin deficiency | THBD | AD | 188040 | Normal CH50, AH50 | Atypical hemolytic–uremic syndrome |
| Membrane cofactor protein (CD46) deficiency | CD46 | AD/AR | 120920 | Inhibitor of complement alternate pathway, decreased C3b binding | Atypical hemolytic–uremic syndrome, infections, preeclampsia |
| Membrane attack complex inhibitor (CD59) deficiency | CD59 | AR | 107271 | Erythrocytes highly susceptible to complement-mediated lysis | Hemolytic anemia, polyneuropathy |
| CD55 deficiency (CHAPLE disease) | CD55 | AR | 125240 | Hyperactivation of complement on endothelium | Protein losing enteropathy, thrombosis |
Footnotes:
MAC, membrane attack complex; SLE, systemic lupus erythematosus.
Total number of mutant genes in Table 8 : 36.
New disorders: None.
Table 9. Bone marrow failure
| Disease | Genetic defect | Inheritance | Gene OMIM | T cells | B cells | Other affected cells | Associated features | Major category | Subcategory |
|---|---|---|---|---|---|---|---|---|---|
| 1. Bone marrow failure | |||||||||
| Fanconi anemia type A | FANCA | AR | 227650 | Normal to low | Normal to low | HSC | Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage | Bone marrow failure with immune deficiency | Fanconi anemia |
| Fanconi anemia type B | FANCB | XLR | 300514 | ||||||
| Fanconi anemia type C | FANCC | AR | 227645 | ||||||
| Fanconi anemia type D1 | BRCA2 | AR | 605724 | ||||||
| Fanconi anemia type D2 | FANCD2 | AR | 227646 | ||||||
| Fanconi anemia type E | FANCE | AR | 600901 | ||||||
| Fanconi anemia type F | FANCF | AR | 603467 | ||||||
| Fanconi anemia type G | FANCG/XRCC9 | AR | 614082 | ||||||
| Fanconi anemia type I | FANCI | AR | 609053 | ||||||
| Fanconi anemia type J | BRIP1 | AR | 609054 | ||||||
| Fanconi anemia type L | FANCL | AR | 614083 | ||||||
| Fanconi anemia type M | FANCM | AR | 618096 | ||||||
| Fanconi anemia type N | PALB2 | AR | 610832 | ||||||
| Fanconi anemia type O | RAD51C | AR | 613390 | ||||||
| Fanconi anemia type P | SLX4 | AR | 613951 | ||||||
| Fanconi anemia type Q | ERCC4 | AR | 615272 | ||||||
| Fanconi anemia type R | RAD51 | AR | 617244 | ||||||
| Fanconi anemia type S | BRCA1 | AR | 617883 | ||||||
| Fanconi anemia type T | UBE2T | AR | 616435 | ||||||
| Fanconi anemia type U | XRCC2 | AR | 617247 | ||||||
| Fanconi anemia type V | MAD2L2 | AR | 617243 | ||||||
| Fanconi anemia type W | RFWD3 | AR | 617784 | ||||||
| MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy) | SAMD9 | AD GOF | 617053 | Not reported | Not reported | HSC, myeloid cells | Intrauterine growth retardation, gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen | ||
| Ataxia–pancytopenia syndrome | SAMD9L | AD GOF | 611170 | Normal | Low | HSC, myeloid cells | MDS, neurological features | ||
| DKCX1 | DKC1 | XL | 305000 | Normal to low | Normal to low | HSC | Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay | Dyskeratosis congenita | |
| DKCA1 | TERC | AD | 127550 | ||||||
| DKCA2 | TERT | AD/AR | 187270 | ||||||
| DKCA3 | TINF2 | AD | 604319 | ||||||
| DKCA4 | RTEL1 | AD | 616373 | ||||||
| DKCA5 | TINF2 | AD | 268130 | ||||||
| DKCA6 | ACD | AD | 616553 | ||||||
| DKCB1 | NOP10/NOLA3 | AR | 224230 | ||||||
| DKCB2 | NHP2/NOLA2 | AR | 613987 | ||||||
| DKCB3 | WRAP53 | AR | 613988 | ||||||
| DKCB4 | TERT | AR | 613989 | ||||||
| DKCB5 | RTEL1 | AR | 615190 | Low | Nail dystrophy, leukoplakia, bone marrow failure, severe B-cell immunodeficiency, intrauterine growth retardation, growth retardation, microcephaly, cerebellar hypoplasia, and esophageal dysfunction | ||||
| DKCB6 | PARN | AR | 616353 | Normal to low | Developmental delay, microcephaly, and cerebellar hypoplasia | ||||
| DKCB7 | ACD | AR | 616553 | Normal to low | Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay | ||||
| BMFS1 (SRP72-deficiency) | SRP72 | AD | 602122 | NA | NA | Bone marrow failure and congenital nerve deafness | |||
| BMFS2 | ERCC6L2 | AR | 615667 | NA | NA | Bone marrow failure, learning difficulties, microcephaly | |||
| BMFS5 | TP53 | AD | 618165 | NA | Low B | Erythroid hypoplasia, B-cell deficiency | |||
| Coats plus syndrome | STN1 | AR | 613129 | Normal | Normal | Intrauterine growth retardation, premature aging, pancytopenia, hypocellular bone marrow, gastrointestinal hemorrhage due to vascular ectasia, intracranial calcification, abnormal telomeres | |||
| CTC1 | AR | 617053 | Not reported | Not reported | |||||
| MECOM deficiency | MECOM | AD | 616738 | Not reported | B-cell deficiency | Bone marrow failure, thrombocytopenia/pancytopenia, radioulnar synostosis, clinodactyly, cardiac, and renal malformations | |||
| Dyskeratosis congenita, Høyeraal–Hreidarsson syndrome | DCLRE1B | AR | 620133 | Normal to low, reduced CD45RA | B-cell deficiency | Low neutrophils in n:1 | Early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation | ||
| BMF, macrocytosis, leukemia | DUT | AR | 620044 | NA | NA | HSC, stromal cells | Diabetes, bone marrow failure | BMF | |
| Nijmegen breakage syndrome–like disorder | RAD50 | AR | 613078 | Low T-cell counts, normal T-cell proportions and proliferation | B-cell deficiency | Microcephaly, mental retardation, bird-like face, short stature | Progressive BMF and immunodeficiency | ||
Footnotes:
HSC, hematopoietic stem cell; NK, natural killer; CNS, central nervous system; GI, gastrointestinal, MDS, myelodysplastic syndrome; DKCX: X-linked dyskeratosis congenital; DKCA, autosomal dominant dyskeratosis congenita; DKCB, autosomal recessive dyskeratosis congenita; BMFS, bone marrow failure syndrome.
Total number of mutant genes in Table 9 : 47.
New IEIs: 3, DCLRE1B (Apollo), DUT , and RAD50 ( 99 , 121 , 122 ).
Table 10. Phenocopies of IEIs associated with autoantibodies or somatic variants
| Disease | Genetic defect/presumed pathogenesis | Circulating T cells | Circulating B cells | Serum Ig | Associated features/similar IEI |
|---|---|---|---|---|---|
| 1. Phenocopies of IEIs | |||||
| Associated with somatic mutations | |||||
| Autoimmune lymphoproliferative syndrome (ALPS-SFAS) | Somatic mutation in TNFRSF6 | Increased CD4−CD8−double-negative (DN) αβ T cells | Normal, but increased, number of CD5+ B cells | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis/ALPS-FAS (=ALPS) |
| RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in KRAS (GOF) | Normal | B-cell lymphocytosis | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like |
| RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in NRAS (GOF) | Increased CD4−CD8− DN T αβ cells | Lymphocytosis | Normal or increased | Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like |
| Cryopyrinopathy, (Muckle–Wells/CINCA/NOMID-like syndrome) a | Somatic mutation in NLRP3 | Normal | Normal | Normal | Urticaria-like rash, arthropathy, neurological signs |
| Hypereosinophilic syndrome due to somatic mutations in STAT5b | Somatic GOF mutation in STAT5B | Normal | Normal | Normal | Eosinophilia, atopic dermatitis, urticarial rash, diarrhea |
| VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome | Somatic GOF mutation in UBA1 (XL) | Lymphopenia | Reduced | Normal | Late-onset treatment-refractory inflammatory syndrome (fevers, neutrophilic dermatosis, macrocytic anemia, dysplastic bone marrow, interstitial nephritis, chondritis, vasculitis) |
| TLR8 GOF | Somatic GOF mutation in TLR8 | ↑ (mild) CD4+, CD8+ T cells, effector/memory subsets; ↓NK cells | Normal B cells/subsets, ↓ pDCs | Normal/lo IgG, ↑ IgM/IgA | Severe cytopenias, hepatosplenomegaly, lymphadenopathy; recurrent infections; hypocellular bone marrow, elevated proinflammatory serum cytokines |
| JAK1 GOF (S703I) a | Somatic GOF mutation in JAK1 | Upregulated STAT3 phosphorylation in T cells | Upregulated STAT6 phosphorylation | Asymmetric pustular rash (inflammatory linear verrucous epidermal nevus) chronic GI tract inflammation, eosinophilic colitis. Peripheral eosinophilia. Membranous glomerulonephritis, asthma | |
| Associated with autoantibodies | |||||
| Chronic mucocutaneous candidiasis | AutoAb to IL-17A and/or IL-17F | Normal | Normal | Normal | Endocrinopathy, chronic mucocutaneous candidiasis/CMC |
| Adult-onset immunodeficiency with susceptibility to environmental mycobacteria | AutoAb to IFN-γ | Decreased naïve T cells | Normal | Normal | Susceptibility to intramacrophagic pathogens (mycobacteria, fungi, Talaromyces marneffei, Salmonella), VZV infections/MSMD, or CID |
| Recurrent staphylococcal skin infection | AutoAb to IL-6 | Normal | Low | Normal | Staphylococcal infections/STAT3 deficiency |
| Pulmonary alveolar proteinosis | AutoAb to GM-CSF | Normal | Normal | Normal | Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency |
| Acquired angioedema | AutoAb to C1 inhibitor | Normal | Normal | Normal | Angioedema/C1 INH deficiency (hereditary angioedema) |
| Atypical hemolytic uremic syndrome | AutoAb to complement factor H (CFH) | Normal | Normal | Normal | aHUS = spontaneous activation of the alternative complement pathway |
| Thymoma with hypogammaglobulinemia (Good’s syndrome) | AutoAb to various cytokines b including type I IFNs | Decreased CD4+ T cells, increased CD8+ T cells | No B cells | Decreased | Invasive bacterial, viral, or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea |
| Critical viral infections | AutoAb to type 1 IFNs (IFN-α, IFN-ω) | • Severe, life-threatening SARS-CoV-2 infection • Critical/“breakthrough” COVID-19 pneumonia • Adverse reactions to yellow fever YFV-17D live-attenuated viral vaccine • Critical influenza pneumonia • Critical Middle East respiratory syndrome (MERS) pneumonia • West Nile virus (WNV) encephalitis | |||
| Sporadic infectious mononucleosis and chronic EBV infection | AutoAb to IL-27 | Infectious mononucleosis, chronic EBV active infection/IL-27RA deficiency | |||
Footnotes:
Abbreviations for all tables: XL, X-linked; AR, autosomal recessive; AD, autosomal dominant; LOF, loss of function; GOF, gain of function; PRCA, pure red cell aplasia; autoAb, autoantibody; aHUS, atypical hemolytic–uremic syndrome; ALPS, autoimmune lymphoproliferative syndrome; CID, combined immunodeficiency.
Total number of conditions for Table 10 : 17 (8 due to somatic mutations; 9 due to autoantibodies).
New phenocopies: 2, 1 due to somatic mutation in JAK1 ( 100 ) and 1 due to autoantibodies against IL-27 ( 68 ). Antibodies against type I interferons previously described for patients with severe COVID-19 were now also described in patients with other severe viral infections; hence, this entry was modified to include SARS-CoV-2 breakthrough infections and others ( 123 , 124 ).
Phenocopies of germline disease.
Autoantibodies against IL-23 were described in the context of thymoma ( 125 ).
Ниже — перевод и комментарии к классификации врожденных ошибок иммунитета, представленной в конце 2019 года с обновлениями 2020 года.
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