Background
Disease | Genetic defect/Presumed pathogenesis Gene OMIM | Inheritance | Circulating T cells | Circulating B cells | Serum Ig | Associated Features | Phenotype OMIM number |
---|---|---|---|---|---|---|---|
T−B+ Severe Combined Immunodeficiency (SCID) | |||||||
γc deficiency | Mutation of IL2RG
Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21 308380 | XL | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells; | 300400 |
JAK3 deficiency | Mutation of JAK3
Defect in Janus activating kinase 3 600173 | AR | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells; | 600802 |
IL7Rα deficiency | Mutation of IL7RA
Defect in IL-7 receptor α chain 146661 | AR | Markedly decreased | Normal or increased | Decreased | Normal NK cells | 608971 |
CD45 deficiency | Mutation of PTPRC
Defect in CD45 151460 | AR | Markedly decreased | Normal | Decreased | Normal γ/δ T cells | 608971 |
CD3δ deficiency | Mutation of CD3D
Defect in CD3δ, chain of T cell antigen receptor complex 186790, | AR | Markedly decreased | Normal | Decreased | Normal NK cells No γ/δ T cells | 615617 |
CD3ε deficiency | Mutation of CD3E
Defect in CD3ε chain of T cell antigen receptor complex 186830, | AR | Markedly decreased | Normal | Decreased | Normal NK cells No γ/δ T cells | 615615 |
CD3ζ deficiency | Mutation of CD3Z
Defect in CD3ζ chain of T cell antigen receptor complex 186780 | AR | Markedly decreased | Normal | Decreased | Normal NK cells No γ/δ T cells | 610163 |
Coronin-1A deficiency | Mutation of CORO1A Defective thymic egress of T cells and defective T cell locomotion 605000 | AR | Markedly decreased | Normal | Decreased | Detectable thymus EBV-associated B-cell lymphoproliferation | 615401 |
T−B− SCID | |||||||
DNA recombination defects (for additional DNA repair defects see Table 2) | |||||||
RAG 1 deficiency | Mutation of RAG1
Defective VDJ recombination; defect of recombinase activating gene (RAG) 1 179615 | AR | Markedly decreased | Markedly decreased | Decreased | 601457 | |
RAG 2 deficiency | Mutation of RAG2
Defective VDJ recombination; defect of recombinase activating gene (RAG) 2 179616 | AR | Markedly decreased | Markedly decreased | Decreased | 601457 | |
DCLRE1C (Artemis) deficiency | Mutation of ARTEMIS
Defective VDJ recombination; defect in Artemis DNA recombinase-repair protein 605988 | AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity | 602450 |
DNA PKcs deficiency | Mutation of PRKDC Defective VDJ recombination; defect in DNA PKcs Recombinase repair protein 600899 | AR | Markedly decreased | Markedly decreased | variable | Radiation sensitivity, microcephaly and developmental defects Autoimmunity and granuloma | 615966 |
Cernunnos/XLF deficiency | Mutation of Cernunnos Defective VDJ recombination; defect in Cernunnos 611290 | AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity, microcephaly and developmental defects | 611291 |
DNA ligase IV deficiency | Mutation of LIG4 Defective VDJ recombination; defect in DNA ligase IV 601837 | AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity, microcephaly and developmental defects | 606593 |
Reticular dysgenesis, AK2 deficiency | Mutation of AK2
Defective maturation of lymphoid and myeloid cells (stem cell defect) Defect in mitochondrial adenylate kinase 2. 103020 | AR | Markedly decreased | Decreased or normal | Decreased | Granulocytopenia and deafness | 267500 |
Adenosine deaminase (ADA) deficiency | Mutation of ADA
Absent ADA activity, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine) 608958 | AR | Absent from birth (null mutations) or progressive decrease | Absent from birth of progressive decrease | Progressive decrease | Decreased NK cells, often with costochondral junction flaring, neurological features, hearing impairment, lung and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation | 102700 |
Combined immunodeficiencies generally less profound than severe combined immunodeficiency | |||||||
DOCK2 deficiency | Mutations in DOCK2 required for RAC1 activation, actin polymerization, T-cell proliferation, chemokine-induced lymphocyte migration and NK-cell degranulation 603122 | AR | Decreased. Poor response to PHA. Low TRECs | Normal | Decreased/ Normal. Poor antibody responses | Normal NK numbers, but defective function. Impaired interferon responses in hematopoietic and non-hematopoietic cells | 616433 |
CD40 ligand deficiency | Mutation of CD40LG Defects in CD40 ligand (CD40L; also called TNFSF5 or CD154) cause defective isotype switching and impaired dendritic cell signaling 300386 | XL | Normal; may progressively decrease | sIgM+ and sIgD+ B cells present, other surface isotype positive B cells absent | IgM increased or normal, other isotypes decreased | Neutropenia, thrombocytopenia; hemolytic anemia, biliary tract and liver disease, opportunistic infections | 308230 |
CD40 deficiency | Mutation of CD40 (also called TNFRSF5) Defects in CD40 cause defective isotype switching and impaired dendritic cell signaling 109535 | AR | Normal | IgM+ and IgD+ B cells present, other isotypes absent | IgM increased or normal, other isotypes decreased | Neutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections | 606843 |
ICOS deficiency | Mutations in ICOS; a co-stimulatory molecule expressed on T cells 604558 | AR | Normal | Normal | Low | Recurrent infections; autoimmunity, gastroenteritis, may have granulomas | 607594 |
CD3γ deficiency | Mutation of CD3G. Defect in CD3γ component of the T cell antigen receptor complex 186740 | AR | Normal, but reduced TCR expression | Normal | Normal | 615607 | |
CD8 deficiency | Mutation of CD8A. Defects of CD8 α chain, important for maturation and function of CD8 T cells 186910 | AR | Absent CD8, normal CD4 cells | Normal | Normal | ||
ZAP-70 deficiency | Mutation in ZAP70 intracellular signaling kinase, acts downstream of TCR 176947 | AR | Decreased CD8, normal CD4 cells | Normal | Normal | Autoimmunity in some cases | 269840 |
MHC class I deficiency | Mutations in TAP1, gene, causing MHC class I non-expression 170260 | AR | Decreased CD8, normal CD4 cells; absent MHC I expression on lymphocytes | Normal | Normal | Vasculitis; pyoderma gangrenosum | 604571 |
MHC class I deficiency | Mutations in TAP2, gene, causing MHC class I non-expression 170261 | AR | Decreased CD8, normal CD4 cells; absent MHC I expression on lymphocytes | Normal | Normal | Vasculitis; pyoderma gangrenosum | 604571 |
MHC class I deficiency | Mutations in TAPBP (tapasin) gene, causing MHC class I non-expression 601962 | AR | Decreased CD8, normal CD4 cells; absent MHC I expression on lymphocytes | Normal | Normal | Vasculitis; pyoderma gangrenosum | 604571 |
MHC class I deficiency | Mutations in B2M gene, causing MHC class I non-expression 109700 | AR | Decreased CD8, normal CD4 cells; absent MHC I expression on lymphocytes | Normal | Normal | Sinopulmonary infections, cutaneous granuloma, hypoproteinemia. Absent expression of β2m associated proteins like MHC-I, CD1a, and CD1b, CD1c on β2m-deficient cells | not yet assigned |
MHC class II deficiency group A | Mutation in transcription factors for MHC class II proteins (CIITA gene) 600005 | AR | Decreased CD4 cells Absent MHC II expression on lymphocytes | Normal | Normal or decreased | Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease | 209920 |
MHC class II deficiency group B | Mutation in transcription factors for MHC class II proteins RFXANK gene 603200 | AR | Decreased CD4 cells Absent MHC II expression on lymphocytes | Normal | Normal or decreased | Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease | 209920 |
MHC class II deficiency group C | Mutation in transcription factors for MHC class II proteins RFX5, gene) 601863 | AR | Decreased CD4 cells Absent MHC II expression on lymphocytes | Normal | Normal or decreased | Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease | 209920 |
MHC class II deficiency group D | Mutation in transcription factors for MHC class II proteins (RFXAP gene 601861 | AR | Decreased CD4 cells Absent MHC II expression on lymphocytes | Normal | Normal or decreased | Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease | 209920 |
ITK deficiency | Mutations in ITK encoding IL-2 inducible T cell kinase required for TCR-mediated activation 186973 | AR | Progressive decrease | Normal | Normal or decreased | EBV associated B cell lymphop-roliferation, lymphoma Normal or decreased IgG | 613011 |
MAGT1 deficiency | Mutations in MAGT1, Impaired Mg++ flux leading to impaired TCR signaling 300715 | XL | Decreased CD4 cells reduced numbers of RTE, impaired T-cell proliferation in response to CD3 | Normal | Normal | EBV infection, lymphoma; viral infections, respiratory and GI infections, | 300853 |
DOCK8 deficiency | Mutations in DOCK8 encoding a dedicator of cytokinesis regulator of intracellular actin reorganisation 611432 | AR | Decreased; Impaired T lymphocyte proliferation; Treg deficiency and poor function | Decreased; low CD27+ memory B cells | Low IgM, increased IgE | Decreased NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and staphylococcal infections, susceptibility to cancer. Defects in peripheral B tolerance. | 243700 |
RhoH deficiency | Mutations in RHOH – an atypical Rho GTPase transducing signals downstream of various membrane receptors 602037 | AR | Normal low naïve T cells and RTE, restricted T cell repertoire and impaired T cells proliferation in response to CD3 stimulation. | Normal | Normal | HPV infection, lymphoma, lung granulomas, molluscum contagiosum, | not yet assigned |
MST1 deficiency | Mutations in STK4 – a serine/threonine kinase 604965 | AR | Decreased increased proportion of terminal differentiated effector memory cells (TEMRA), low naïve T cells, restricted T cell repertoire in the TEMRA population and impaired T cells proliferation | Decreased | High | Recurrent bacterial, viral, and candidal infections; intermittent neutropenia; EBV-driven lymphoproliferation; lymphoma; Congenital heart disease, autoimmune cytopenias; HPV infection. | 614868 |
TCRα deficiency | Mutations in TRAC – essential component of the T cell receptor 186880 | AR | Normal All CD3 T cells expressed TCRγδ (or may be better to say: TCRαβ T-cell deficiency), impaired T cells proliferation | Normal | Normal | Recurrent viral, bacterial and fungal infections, immune dysregulation autoimmunity, and diarrhea. | 615387 |
LCK deficiency | Defects in LCK – a proximal tyrosine kinase that interacts with TCR 153390 | AR | Normal total numbers but CD4+ T-cell lymphopenia, low Treg numbers, restricted T cell repertoire and impaired TCR signaling | Normal | Normal IgG and IgA and increased IgM | Diarrhea, recurrent infections, immune dysregulation autoimmunity, | 615758 |
MALT1 deficiency | Mutations in MALT1 – a caspase-like cysteine protease that is essential for nuclear factor-kappa-B activation 604860 | AR | Normal number but impaired T cells proliferation | Normal | Normal Impaired antibody response | Bacterial, fungal and viral infections | 615468 |
CARD11 deficiency | Defects in CARD11 – acts as a scaffold for NF-КB activity in the adaptive immune response 607210 | AR | Normal predominance of naive T-lymphocyte, impaired T cells proliferation | Normal predominance of transitional B lymphocytes, | Absent/low | Pneumocystis jirovicii pneumonia, bacterial infections, | 615206 |
BCL10 deficiency | Mutations in BCL10 which encodes the B cell CLL / lymphoma 10 protein that forms a heterotrimer with Malt1 and CARD family adaptors and plays a role in NF-kB signaling 603517 | AR | Normal numbers, low memory T and Tregs, decreased proliferation to antigen and anti-CD3 | Normal number; decreased memory and switched B cells | Low | Recurrent bacterial and viral infections, candidiasis, gastroenteritis | 616098 |
IL-21 deficiency | Mutation in IL21
605384 | AR | Normal number. Normal/low function | Low | IgG deficiency | Severe early onset colitis | 615767 |
IL-21R deficiency | Defects in IL21R – together with common gamma chain binds IL-21 605383 | AR | Abnormal T cell cytokine production; Abnormal T cell proliferation to specific stimuli | Normal | Normal but impaired specific responses | Suspectibility to cryptoporidia and pneumocystis and cholangitis | 615207 |
OX40 deficiency | Defects in OX40 (TNFRSF4) encoding a co-stimulatory molecule expressed on activated T cells 600315 | AR | Normal T cell numbers; decreased antigen specific memory CD4+ cells | Normal B cell numbers; reduced frequency of memory B cells | Normal | Kaposi’s sarcoma; impaired immunity to HHV8 | 615593 |
IKBKB deficiency | Defects in IKBKB, encoding IkB 2 kinase 2, a component of the NF-kB pathway 603258 | AR | Normal total T cells; absent regulatory and γδ T cells; impaired TCR activation | Normal B cell numbers; impaired BCR activation; | Decreased | Recurrent bacterial, viral and fungal infections; clinical phenotype of SCID | 615592 |
LRBA deficiency | Mutations in LRBA (lipopolysaccharide responsive beige-like anchor protein) 606453 | AR | Normal or decreased CD4 numbers; T cell dysregulation | Low or normal numbers of B cells | Reduced I IgG and IgA in most | Recurrent infections, inflammatory bowel disease, autoimmunity; EBV infections | 614700 |
CD27 deficiency | Mutations in CD27 (TNFRSF7) encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunity 186711 | AR | Normal | No memory B cells | Hypogamma-globulinaemia following EBV infection | Clinical and immunologic features triggered by EBV infection, HLH Aplastic anaemia, Lymphoma, hypogammaglobulinemia, Low iNKT cells | 615122 |
NIK deficiency | Mutation in MAP3K14, encoding NIK (NF-kB-inducing kinase) 604655 | AR | Normal number; impaired proliferation in response to antigen stimulation. Polycloncal Vβ repertoires | Decreased total peripheral B cell and switched memory B cells | Hypogamma-globulinaemia | Recurrent bacterial, viral and Cryptosporidium infections. Low NK cell number and defective NK cell activation | Not yet assigned |
CTPS1 deficiency | Mutation in CTPS1, encoding CTP synthase 1, essential for lymphocyte proliferation 123860 | AR | Normal or decreased number Normal or decreased proliferation | Normal/low number | Normal/high IgG | Recurrent/chronic viral infections specially EBV and VZV, bacterial infections, EBV-driven B-cell non-Hodgkin lymphoma | 615897 |
Omenn syndrome | Hypomorphic mutations in RAG1, RAG2, Artemis, IL7RA, RMRP, ADA, DNA Ligase IV, IL2RG, AK2, or associated with DiGeorge syndrome; some cases have no defined gene mutation | Present; restricted T cell repertoire and impaired function | Normal or decreased | Decreased, except for increased IgE | Erythroderma, eosinophilia, adenopathies, hepatosplenomegaly | 603554 |
Disease | Genetic defect/Presumed pathogenesis OMIM number gene locus | Inheritance | Circulating T cells | Circulating B cells | Serum Ig | Associated features | OMIM number Phenotype |
---|---|---|---|---|---|---|---|
1. Congenital thrombocytopenia | |||||||
Wiskott-Aldrich syndrome (WAS) | Mutations in WAS; cytoskeletal and immunologic synapse defect affecting haematopoietic stem cell derivatives 301000 | XL | Progressive decrease, Abnormal lymphocyte responses to anti-CD3 | Normal numbers | Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE | Thrombocytopenia with small platelets; eczema; lymphoma; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP | 300392 |
WIP deficiency | Mutations in WIPF1; cytoskeletal and immunologic synapse defect affecting haematopoietic stem cell derivatives 602357 | AR | Reduced, Defective lymphocyte responses to anti-CD3 | Low | Normal, except for increased IgE | Recurrent infections; eczema; thrombocytopenia. WAS-like phenotype. | 614493 |
2. DNA repair defects (other than those in Table 1) | |||||||
Ataxia-telangiectasia | Mutations in ATM; disorder of cell cycle check-point and DNA double- strand break repair 607585 | AR | Progressive decrease, abnormal proliferation to mitogens | Normal | Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased | Ataxia; telangiectasia; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein and increased radiosensitivity; chromosomal instability | 208900 |
Nijmegen breakage syndrome | Hypomorphic mutations in NBS1
(Nibrin); disorder of cell cycle checkpoint and DNA double- strand break repair 602667 | AR | Progressive decrease | Variably reduced | Often decreased IgA, IgE and IgG subclasses; increased IgM; antibodies variably decreased | Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensitivity; chromosomal instability | 251260 |
Bloom syndrome | Mutations in BLM (RECQL3); encoding DNA helicase RecQ protein-like 3 helicase 604610 | AR | Normal | Normal | Reduced | Short stature; bird like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability | 210900 |
Immunodeficiency with centromeric instability and facial anomalies (ICF1) | Mutations in DNA methyltransferaseDNMT3B (ICF1) resulting in defective DNA methylation 602900; | AR | Decreased or normal; responses to PHA may be decreased | Decreased or normal | Hypogammaglobulinemia; variable antibody deficiency | Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks | 242860 |
Immunodeficiency with centromeric instability and facial anomalies (ICF2) | Mutations in ZBTB24 (ICF2) 614064 | AR | Decreased or normal; Responses to PHA may be decreased | Decreased or normal | Hypogammaglobulinemia; variable antibody deficiency | Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; | 614069 |
PMS2 deficiency | Mutations in PMS2, resulting in Class Switch recombination deficiency due to impaired mismatch repair 600259 | AR | Normal | Reduced B cells, switched and non-switched | Low IgG and IgA, elevated IgM, abnormal antibody responses | Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor | 276300 |
RNF168 deficiency | Mutations in RNF168, resulting in defective DNA double-strand break repair (RIDDLE syndrome) 612688 | AR | Normal | Normal | Low IgG, IgM, or low IgA | Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity | 611943 |
MCM4 deficiency | Mutations in MCM4 (minichromosome maintenance complex component 4) gene involved in DNA replication and repair 602638 | AR | Normal | Normal | Normal | Viral infections (EBV, HSV, VZV) Adrenal failure Short stature Low NK cells | 609981 |
3. Thymic defects with additional congenital anomalies | |||||||
DiGeorge syndrome* | Contiguous gene deletion in chromosome 22q11.2 or mutation of a gene within this deletion region, TBX1, encoding a transcription factor critical for development of thymus and adjacent embryonic structures 602054 |
De novo haplo-insufficiency (majority) or AD; phenocopies may have other as yet undefined genetic lesions | Decreased or normal; 5 % have <1500 CD3 T cells/uL in neonatal period | Normal | Normal or decreased | Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability and other abnormalities; often with 3 Mb interstitial deletion in 22q11.2 (or rarely with intragenic mutation of TBX1, deletion in 10p) | 188400 |
CHARGE syndrome due to CHD7 defects | Variable defects of the thymus and associated T cell abnormalities, often due to deletions or mutations in transcription regulator CHD7, 608892 |
De novo haplo-insufficiency (majority) or AD | Decreased or normal; response to PHA may be decreased | Normal | Normal or decreased | Coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies; some are SCID-like and have low TRECs | 214800 |
CHARGE syndrome due to SEMA3E defects | Variable defects of the thymus and associated T cell abnormalities, often due to deletions or mutations in transcription regulator, or semaphorin SEMA3E 608166 |
De novo haplo-insufficiency (majority) or AD | Decreased or normal; response to PHA may be decreased | Normal | Normal or decreased | Coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies; some are SCID-like and have low TRECs | 214800 |
Winged helix deficiency (nude) AAB: syndromic SCID | Defects in forkhead box N1 transcription factor encoded by FOXN1
600838 | AR | Markedly decreased | Normal | Decreased | Alopecia; nail dystropphy; severe infections abnormal thymic epithelium, impaired T cell maturation | 601705 |
4. Immune-osseous dysplasias | |||||||
Cartilage hair hypoplasia | Mutations in RMRP (RNase MRP RNA) Involved in processing of mitochondrial RNA and cell cycle control 157660 | AR | Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation | Normal | Normal or reduced antibodies variably decreased | Short-limbed dwarfism with metaphysealdysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine | 250250 |
Schimke Immunoosseous Dysplasia | Mutations in SMARCAL1; involved in chromatin remodeling 606622 | AR | Decreased | Normal | Normal | Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure | 242900 |
5. Hyper-IgE syndromes (HIES) | |||||||
AD-HIES (Job or Buckley Syndrome) | Dominant-negative heterozygous mutations in signal transducer and activator of transcription STAT3
102582 | AD Often de novo mutation | Normal overall Th-17 and T-follicular helper cells decreased | Normal; reduced switched and non-switched memory B cells; BAFF expression increased | Elevated IgE; specific antibody production decreased | Distinctive facial features (broad nasal bridge), bacterial infections (boils and pulmonary abscesses, pneumatoceles) due to S. aureus, aspergillus, Pneumocystis jirovecii; eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, aneurysm formation | 147060 |
Comel-Netherton syndrome | Mutations in SPINK5 resulting in lack of the serine protease inhibitor LEKTI, expressed in epithelial cells 605010 | AR | Normal | Switched and non-switched B cells are reduced | Elevated IgE and IgA Antibody variably decreased | Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive | 256500 |
PGM3 deficiency | Mutations inphosphoglycomutase 3 (PGM3) associated with a glycosylationand atopy 172100 | AR | CD8 and CD4 T cells may be decreased | Reduced B and memory B cells | Normal or elevated Ig’s, elevated IgE; eosinophilia | Severe atopy, autoimmunity, bacterial and viral infections, cognitive impairment, hypomyelination | 615816 |
6. Dyskeratosis congenita (DKC) with bone marrow failure and dysfunctional telomere maintenance | |||||||
XL-DKC due to Dyskerin deficiency | Mutations in DKC1 encoding dyskerin 300126 | XL | Progressive decrease | Progressive decrease | Variable hypogammag-lobulinemia | Intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells. A severe phenotype with developmental delay and cerebellar hypoplasia is known as Hoyeraal-Hreidarsson Syndrome (HHS) | 305000 |
AR-DKC due to nucleolar protein family A member 2 (NHP2) deficiency | Mutations in NOLA2 (NHP2), component of the H/ACA ribonucleo-protein complex 606470 | AR | Decreased | Variable | Variable | Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails | 613987 |
AR-DKC due to nucleolar protein family A member 3 (NHP3) or NOP10 deficiency | Mutation in NOLA3 (NOP10, PCFT), a component of the H/ACA ribonucleo-protein complex 606471 | AR | Decreased | Variable | Variable | Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails | 224230 |
AR-DKC due to regulator of telomere elongation (RTEL1) deficiency | Mutation in RTEL1 encoding regulator of telomere elongation helicase 1 (RTEL1) 608833 | AD or AR | Decreased | Variable | Variable | Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails. May present as HHS | 615190 |
AD-DKC due to TERC deficiency | Mutation in TERC encoding telomerase RNA component 602322 | AD | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS | 127550 |
AD-DKC due to TERT deficiency | Mutation in TERT encoding telomerase reverse transcriptase 187270 | AD or AR | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. AD version is milder than the AR version which can resemble HHS | 613989 |
AD-DKC due to TINF2 deficiency | Mutation in TINF2 encoding telomerase interacting factor 2 604319 | AD | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS | 613990 |
AD/AR -DKC due to TPP1 deficiency | Mutation in adrenocortical dysplasia homolog (ACD) encoding TPP1 affecting the TELpatch domain resulting in failure to recruit telomerase to telomers 609377 | AD/AR | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis leukoplakia of the oralmucosa, carcinoma, leukemia palmar hyperkeratosis, anemia, pancytopenia. May present as HHS | |
AR-DKC due to DCLRE1B deficiency | Mutation in DCLRE1B/ SNM1/APOLLO: DNA CROSS-LINK REPAIR PROTEIN 1B 609683 | AR | dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome | 616353 | |||
AR-DKC due to PARN deficiency | Mutation in PARN, POLYADENYLATE-SPECIFIC RIBONUCLEASE 604212 | AR | 616353 | ||||
7. Defects of Vitamin B12 and Folate metabolism | |||||||
Transcobalamin 2 (TCN2) deficiency | Mutation in TCN2; encoding a transporter of cobalamin into blood cells 613441 | AR | Normal | Variable | Decreased | Megaloblastic anaemia, pancytopaenia, if untreated for prolonged periods results in mental retardation | 275350 |
SLC46A1/PCFT deficiency causing hereditary folate malabsorbtion | Mutation in SLC46A1, encoding a proton coupled folate transporter | AR | Variable numbers and activation profile | Variable | Decreased | Megaloblastic anaemia, failure to thrive, if untreated for prolonged periods results in mental retardation | 229050 611672 |
Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency | Mutations in enzyme encoded by MTHFD, essential for processing single-carbon folate derivatives | AR | Low | Low | Decreased | Megaloblastic anaemia, failure to thrive, neutropenia, seizures, mental retardation | 601634 172460 |
8. Anhidrotic ectodermaldysplasia with immunodeficiency (EDA-ID) | |||||||
(EDA-ID. NEMO /IKBKG deficiency | Mutations of NEMO (IKBKG), a modulator of NF-κB activation Defects in IKBKG, encoding NEMO, a component of the NF-κB pathway Mutations of NEMO (IKBKG), a modulator of NF-κB activation 300248 | XL | Normal or decreased; poor CR activation function | Normal Low B memory B cells | Decreased; poor specific antibody responses, absent antibody to polysaccharide antigens | anhidrotic ectodermal dysplasia + specific antibody deficiency (lack of Ab response to polysac-charides) + various infections (mycobacteria and pyogens) Various infections (bacteria, mycobacteria, viruses and fungi); colitis, EDA (not in all patients); conical teeth, variable defects of skin pigmentation, monocyte dysfunction | 300291, 300584, 300301 300640 |
EDA-ID IKBA gain of function mutation | Gain of function mutation in IKBA (NFKIAB), encoding IκBα, a component of the NF-κB pathway Gain-of-function mutation of IKBA, resulting in impaired activation of NF-κB 164008 | AD | Normal total T cells;; impaired TCR activation | Normal B cell numbers; impaired BCR activation; | Decreased; poor specific antibody responses, absent antibody to polysaccharide antigens | Various infections (bacteria, mycobacteria, viruses and fungi); colitis, EDA (not in all patients); variable defects of skin, hair and teeth, T cell and monocyte dysfunction Anhidrotic ectodermal dysplasia + T cell defect + various infections: Recurrent bacterial, viral and fungal infections; | 612132 |
9. Calcium channel defects | |||||||
ORAI-I deficiency | Mutation in ORAI1, a Ca++ release-activated channel (CRAC) modulatory component 610277 | AR | Normal; defective TCR mediated activation | Normal | Normal | Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy | 612782 |
STIM1 deficiency | Mutations in STIM1, a stromal interaction molecule 1 605921 | AR | Normal; defective TCR mediated activation | Normal | Normal | Autoimmunity, anhydrotic ectodermal dysplasia, non-progressive myopathy | 612783 |
10. Other defects | |||||||
Hepatic veno-occlusive disease with immunodeficiency (VODI) | Mutations in nuclear body protein encoded by SP110
604457 | AR | Normal (decreased memory T cells) | Normal (decreased memory B cells) | Decreased IgG, IgA, IgM; absent germinal centers and tissue plasma cells | Hepatic veno-occlusive disease; Susceptibility to Pneumocystis jiroveci pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystropy | 235550 |
Facial dysmorphism, immunodeficiency, livedo, short stature (FILS) syndrome | Mutation in POLE1; Defective DNA replication 174762 | AR | Low naïve T cells; decreased T cell proliferation | Low memory B cells | Decreased IgM and IgG; Lack of antibodies to polysaccharide antigens | Mild facial dysmorphism (malar hypoplasia, high forehead), livedo, short stature; recurrent upper and lower respiratory tract infections, recurrent pulmonary infections and recurrent meningitis | 615139 |
Immunodeficiency with multiple intestinal atresias | Mutation in TTC7A (tetratricopeptide repeat (TPR) domain 7A) protein, of unkown function 609332 | AR | Variable, but sometimes absent | Normal | Decreased | Multiple intestinal atresias, often with intrauterine polyhydramnios and early demise; some with SCID phenotype | 243150 |
Vici syndrome due to EPG5 deficiency | Mutations in EPG5 encoding ectopic P-granules autophagy protein 5, involved in the formation of autolysosomes required for autophagy | AR | Profound depletion of CD4+ cells | Defective | Decreased (particularly IgG2) | Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation, cleft lip/palate, recurrent infections, chronic mucocutaneous candidiasis | 242840 615068 |
Purine nucleoside phosphorylase (PNP) deficiency | Mutation of PNP leading to absent PNP, T cell and neurologic defects from elevated toxic metabolites, especially dGTP 164050 | AR | Progressive decrease | Normal | Normal or decreased | Autoimmune haemolytic anemia, neurological impairment | 613179 |
HOIL1 deficiency | Mutation of HOIL1/RBCK1, encoding a component of the linear ubiquitination chain assembly complex LUBAC, resulting in impaired activation of NF-κB 610924 | AR | Normal numbers, | Normal, but decreased memory B cells | Poor antibody production to polysaccharide antigens | Bacterial infections (pyogens), autoinflammation. amylopectinosis | 615895 |
HOIP deficiency | Mutation of HOIP1 (/RNF31), encoding a component of the linear ubiquitination chain assembly complex LUBAC, resulting in impaired activation of NF-κB 612487 | AR | Normal numbers | Normal, but decreased memory B cells | decreased | Bacterial infections (pyogens), autoinflammation. Amylopectinosis, Lymphangiectasia | Not yet assigned |
Hennekam-lymphangiectasia-lymphedema syndrome | Mutation of CCBE1: (COLLAGEN AND CALCIUM-BINDING EGF DOMAIN-CONTAINING PROTEIN1) 612753 | AR | Low/variable | Low/variable | decreased | Lymphangiactasia and lymphedema with facial abnormalities and other dysmorphic features | 235510 |
STAT5b deficiency | Mutations in STAT5B signal transducer and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cells, as well as other cytokines 604260 | AR | Modestly decreased | Normal | Normal | Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity | 245590 |
Disease | Genetic defect/Presumed pathogenesis Gene OMIM | Inheritance | Serum Ig | Associated features | Phenotype OMIM number |
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells | |||||
BTK deficiency | Mutations in BTK, a cytoplasmic tyrosine kinase activated by crosslinking of the BCR 300300 | XL | All isotypes decreased in majority of patients; some patients have detectable immunoglobulins | Severe bacterial infections; normal numbers of pro-B cells | 300755 |
μ heavy chain deficiency | Mutations in μ heavy chain (IGHM); essential component of the pre-BCR 147020 | AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | 601495 |
λ5 deficiency | Mutations in λ5 (IGLL1); part of the surrogate light chain in the pre-BCR 146770 | AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | 613500 |
Igα deficiency | Mutations in Igα (CD79A); part of the pre-BCR and BCR 112205 | AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | 112205 613501 |
Igβ deficiency | Mutations in Igb (CD79B); part of the pre-BCR and BCR 147245 | AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | 612692 |
BLNK deficiency | Mutations in BLNK; a scaffold protein that binds to BTK 604615 | AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | 613502 |
PI3KR1 deficiency | Mutations in PIK3R1; a kinase involved in signal transduction in multiple cell types. Complete loss of PI3K p85-alpha resulting in complete loss of B cell development 171833 | AR | All isotypes decreased | Severe bacterial infections; decreased or absent pro-B cells | 615214 |
E47 transcription factor deficiency | Mutations in TCF3; a transcription factor required for control of B cell development 147141 | AD | All isotypes decreased | Recurrent bacterial infections | Not yet assigned |
Thymoma with immunodeficiency | Unknown | None | One or more isotypes may be decreased | Bacterial and opportunistic infections; autoimmunity; decreased number of pro-B cells | |
Disease | Genetic defect/Presumed pathogenesis | Inheritance | Serum Ig | Associated features | OMIM number |
2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells | |||||
Common variable immuno-deficiency disorders | Unknown | Variable | Low IgG and IgA and/or IgM | Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease | |
CD19 deficiency | Mutations in CD19; transmembrane protein that amplifies signal through BCR 107265 | AR | Low IgG and IgA and/or IgM | Recurrent infections; May have glomerulonephritis | 613493 |
CD81 deficiency | Mutations in CD81; transmembrane protein that amplifies signal through BCR 186845 | AR | Low IgG, low or normal IgA and IgM | Recurrent infections; May have glomerulonephritis | 613496 |
CD20 deficiency | Mutations in CD20; a B cell surface receptor involved in B cell development and plasma cell differentiation 112210 | AR | Low IgG, normal or elevated IgM and IgA | Recurrent infections | 613495 |
CD21 deficiency | Mutations in CD21; also known as complement receptor 2 and forms part of the CD19 complex 120650 | AR | Low IgG; impaired anti-pneumococcal response | Recurrent infections | 614699 |
TACI deficiency | Mutations in TNFRSF13B (TACI); a TNF receptor family member found on B cells and is a receptor for BAFF and APRIL 604907 | AD or AR or complex | Low IgG and IgA and/or IgM | Variable clinical expression | 240500 |
BAFF receptor deficiency | Mutations in TNFRSF13C (BAFF-R); a TNF receptor family member found on B cells and is a receptor for BAFF 606269 | AR | Low IgG and IgM; | Variable clinical expression | 613494 |
TWEAK deficiency | Mutations in a cytokine TWEAK (TNFSF12); TNF-related weak inducer of apoptosis 602695 | AD | Low IgM and A; lack of anti-pneumococcal antibody | Pneumonia, bacterial infections, warts; thrombocytopenia. neutropenia | not yet assigned |
NFKB2 deficiency | Mutations in NFKB2; an essential component of the noncanonical NF-κB pathway | AD | Low IgG and IgA and IgM; very low B cells in some | Recurrent infections; adrenal insufficiency; ACTH deficiency; alopecia | 615577 |
MOGS deficiency | Mutation in mannosyl-oligosaccharide glucosidase 601336 | AR | Severe hypogammaglobulinemia; | Bacterial and viral infections; severe neurologic disease; also contains glycosylation type IIb (CDG-IIb), | 606056 |
TRNT1 deficiency
| Mutation in TRNT1 a template-independent RNA polymerase required for the maturation of cytosolic and mitochondrial transfer RNAs (tRNAs) 612907 | AR | B cell deficiency and hypogammaglobulinemia | congenital sideroblastic anemia; deafness; developmental delay | 616084 |
TTC37 deficiency |
Mutation in TTC37 gene 614589 | AR | Poor antibody response to pneumococcal vaccine | Recurrent bacterial and viral infections; Abnormal hair findings: trichorrhexis nodosa | 222470 |
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells | |||||
AID deficiency | Mutations in AICDA gene 605257 | AR | IgG and IgA decreased; IgM increased | Bacterial infections; enlarged lymph nodes and germinal centers | 605258 |
UNG deficiency | Mutations in UNG
191525 | AR | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centers | 608106 |
INO80 | INO80 chromatin remodeling complex; mild DNA repair defect 610169 | AR | IgG and IgA decreased; IgM increased | Severe bacterial infections | not yet assigned |
MSH6 | MSH6 gene defect part of mismatch repair [MMR] machinery); DNA repair defect 600678 | AR | Variable IgG, defects; increased IgM in some; normal B cells, low switched memory B cells; Ig-CSR and SHM defects | Family or personal history of cancer | not yet assigned |
4. Isotype or light chain deficiencies with generally normal numbers of B cells | |||||
Activated PI3K-δ | Mutation in PIK3CD;
p110 encoding for p110 subunit of PI3K
602839 | AD gain of function | Reduced IgG2 and impaired antibody to pneumococci and hemophilus | Respiratory infections, bronchiectasis; autoimmunity; chronic EBV, CMV infection | 615513 |
PI3KR1 loss of function | Mutation in PIK3R1 leading to mutations in p85α 171833 | AD loss of function of p85α (leading to activation of PI3K-δ – as above) | Absent IgA, low IgG | EBV, CMV viremia; growth retardation | 616005 |
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 | |
IGKC deficiency | Mutations in Kappa constant gene | AR | All immunoglobulins have lambda light chain | Asymptomatic | 147200 |
Isolated IgG subclass deficiency | Unknown | Variable | Reduction in one or more IgG subclass | Usually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections | |
IgA with IgG subclass deficiency | Unknown | Variable | Reduced IgA with decrease in one or more IgG subclass | Recurrent bacterial infections | |
Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells | Unknown | Variable | Normal | Reduced ability to produce antibodies to specific antigens | |
Transient hypogammaglobulinemia of infancy with normal numbers of B cells | Unknown | Variable | IgG and IgA decreased | Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections | |
CARD 11 gain of function | CARD11; scaffold for NF-kB activity in the adaptive immune response; gain of function | AD | Congenital B cell lymphocytosis. High B cell numbers due to constitutive NF-κB activation | Splenomegaly; lymphadenopathy | 607210; 606445 |
Disease | Genetic defect/Presumed pathogenesis Gene OMIM | Inheritance | Circulating T Cells | Circulating B cells | Functional defect | Associated Features | Phenotype OMIM number |
---|---|---|---|---|---|---|---|
1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes | |||||||
1.1. FHL syndromes without hypopigmentation | |||||||
Perforin deficiency (FHL2) | Mutations in PRF1; perforin is a major cytolytic protein 170280 | AR | Increased activated T cells | Normal | Decreased to absent NK and CTL activities cytotoxicity | Fever, Hepato-Splenomegaly (HSMG), Hemophagocytic lymphohistiocytosis (HLH), Cytopenias | 603553 |
(UNC13D / Munc13-4 deficiency (FHL3) | Mutations in UNC13D; required to prime vesicles for fusion 608897 | AR | Increased activated T cells | Normal | Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, Cytopenias, | 608898 |
Syntaxin 11 deficiency, (FHL4) | Mutations in STX11, required for secretory vesicle fusion with the cell membrane 605014 | AR | Increased activated T cells | Normal | Decreased NK activity (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, Cytopenias, | 603552 |
STXBP2 / Munc18-2 deficiency (FHL5) | Mutations in STXBP2, required for secretory vesicle fusion with the cell membrane 601717 | AR or AD | Increased activated T cells | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, Cytopenias, | 613101 |
SH2D1A deficiency (XLP1) | Mutations in SH2D1A encoding an adaptor protein regulating intracellular signaling 300490 | XL | Normal or increased activated T cells | Reduced Memory B cells | partially defective NK cell and CTL cytotoxic activity | Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, Aplastic anaemia, lymphoma. Hypogammaglobulinemia, absent iNKT cells | 308240 |
XIAP deficiency (XLP2) | Mutations in XIAP/ BIRC4 encoding an inhibitor of apoptosis 300079 | XL | Normal or Increased activated T cells; low/normal iNK T cells | Normal or reduced Memory B cells | Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD) | EBV infection, Splenomegaly, lymphoproliferation HLH, Colitis, IBD, hepatitis Low iNKT cells | 300635 |
1.2. FHL syndromes with hypopigmentation | |||||||
Chediak-Higashi syndrome | Mutations in LYST, impaired lysosomal trafficking 606897 | AR | Increased activated T cells | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism, recurrent infections, fever, HSMG, HLH Giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction | 214500 |
Griscelli syndrome, type2 | Mutations in RAB27A encoding a GTPase that promotes docking of secretory vesicles to the cell membrane 603868 | AR | Normal | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism, fever, HSMG, HLH, cytopenias | 607624 |
Hermansky-Pudlak syndrome, type 2 | Mutations in AP3B1 gene, encoding for the β subunit of the AP-3 complex 603401 | AR | Normal | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism, recurrent infections, pulmonary fibrosis Increased bleeding, neutropenia, HLH | 608233 |
Hermansky-Pudlak syndrome, type 9 | Mutations in PLDN, encoding Pallidin, a component of the biogenesis of lysosome-related organelles complex-1 (BLOC-1) 604310 | AR | (Not assessed; leukopenia) | (Not assessed, leukopenia) | Decreased NK cell cytolytic activity | Oculocutaneous albinism, recurrent cutaneous infections, leukopenia, thrombocytopenia | 614171 |
2. T regulatory cells genetic defects | |||||||
IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked | Mutations in FOXP3, encoding a T cell transcription factor 300292 | XL | 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, IgA | 304790 |
CD25 deficiency | Mutations in IL2RA, encoding IL-2Rα chain, 147730 | AR | Normal to decreased | Normal | No CD4 + C25+ cells with impaired function of Tregs cells | Lymphoproliferation, autoimmunity. Impaired T cell proliferation | 606367 |
CTLA4 deficiency (ALPSV) | Mutations in CTLA4, encoding Cytotoxic T Lymphocyte antigen 4, a protein that negatively regulate T cell receptor signaling and T cell activation. 123890 | AD | Decreased | Decreased | Impaired function of Treg cells. | Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration recurrent infections, | 616100 |
STAT3 GOF mutations | Mutations in STAT3, encoding Signal Transducer and activator 3 102582 | AD | Decreased | Decreased | Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation and autoimmunity. Decreased Treg cell numbers and impaired phenotype | Lymphoproliferation, Solid organ autoimmunity, recurrent infections. | 615952 |
3. Autoimmunity with or without lymphoproliferation | |||||||
APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy | Mutations in AIRE, encoding a transcription regulator needed to establish thymic self-tolerance 607358 | AR | Normal | Normal | AIRE-1 serves as check-point 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, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata Enteropathy, Pernicious anemia, | 240300 |
ITCH deficiency | Mutations in ITCH, an E3 ubiquitin ligase catalyzes the transfer of ubiquitin to a signaling proteins in the cell including phospholipase Cγ1 (PLCγ1) 606409 | AR | Not assessed | Not assessed | Itch deficiency may cause immune dysregulation by affecting both anergy induction in auto-reactive effector T cells and generation of Tregs | Early-onset chronic lung disease (interstitial pneumonitis) Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis) Failure to thrive, developmental delay, dysmorphic facial features | 613385 |
Tripeptidyl-Peptidase II Deficiency | Mutations in TPP2, encoding tripeptidyl-peptidase II, serine exopeptidase involved in extralysosomal peptide degradation 190470 | AR | Decreased | Decreased | TPP2 deficiency results in premature immunosenescence and immune dysregulation | Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections, | Not yet assigned |
3. Autoimmune lymphoproliferative syndrome (ALPS) | |||||||
ALPS-FAS | Germinal mutations in TNFRSF6, encoding CD95/Fas cell surface apoptosis receptor** 134637 | AD AR*** | Increased CD4−CD8−TCRαβ double negative (DN) T cells | Normal, low memory B cells | Apoptosis defect FAS mediated | Splenomegaly, adenopathies, Autoimmune cytopenias, increased lymphoma risk. IgG and A normal or increased Elevated FasL and IL-10, vitamin B12 | 601859 |
ALPS-FASLG | Mutations in TNFSF6, Fas ligand for CD95 apoptosis 134638 | AR | Increased DN T cells | Normal | Apoptosis defect FAS mediated | Splenomegaly, adenopathies, autoimmune cytopenias, SLE; Soluble FasL is not elevated | 601859 |
ALPS-Caspase10 | Mutations in CASP10, intracellular apoptosis pathway 601762 | AD | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Adenopathies, splenomegaly, autoimmunity. | 603909 |
ALPS-Caspase 8 | Mutations in CASP8, intracellular apoptosis and activation pathways 601763 | AR | Slightly increased DN T cells | Normal | Defective lymphocyte apoptosis and activation | Adenopathies, splenomegaly, Bacterial and viral infections, Hypogammaglobulinemia | 607271 |
FADD deficiency | Mutations in FADD encoding an adaptor molecule interacting with FAS, and promoting apoptosis 602457 | AR | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Functional hyposplenism, Bacterial and viral infections, Recurrent episodes of encephalopathy and liver dysfunction. | 613759 |
PRKC delta deficiency | Mutations in PRKCD, encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation and apoptosis 176977 | AR | Normal | Low memory B cells and Elevation of CD5 B cells | Apoptotic defect in B cells | Recurrent infections; EBV chronic infection Lymphoproliferation SLE-like autoimmunity (Nephrotic and antiphospholipid syndromes) HypoIgG | 615559 |
4. Immune dysregulation with colitis | |||||||
IL-10 deficiency | Mutations in IL10, encoding IL-10 124092 | AR | Normal | Normal | No functional IL-10 secretion | Inflammatory bowel disease (IBD) Folliculitis, Recurrent respiratory diseases, Arthritis, | not assigned |
IL-10Rα deficiency | Mutations in IL10RA, encoding IL-10R1 146933 | AR | Normal | Normal | Leukocytes no response to IL-10 | IBD, Folliculitis, Recurrent respiratory diseases, Arthritis, Lymphoma | 613148 |
IL-10Rβ deficiency | Mutations in IL10RB, encoding IL-10R2 123889 | AR | Normal | Normal | Leukocytes no response to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29 | IBD, Folliculitis, Recurrent respiratory diseases, Arthritis, Lymphoma | 612567 |
NFAT5 haploinsufficiency | Hemizygous deletion of NFAT5
604708 | AD | Normal | Normal | Decreased memory B cells and plasmablasts | IBD, recurrent sinopulmonary infections | Not yet assigned |
5. Type 1 Interferonopathies | |||||||
TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1) | Mutations in TREX1, encoding nuclease involves in clearing cellular nucleic debris 606609 | AR AD***** | Not assessed | Not assessed | Intracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, Thrombocytopenia, Elevated hepatic transaminases Chronic cerebrospinal fluid (CSF) lymphocytosis | 225750 |
RNASEH2B deficiency, AGS2 | Mutations in RNASEH2B, encoding nuclease subunit involves in clearing cellular nucleic debris 610326 | AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, Elevated hepatic transaminases Chronic CSF lymphocytosis | 610181 |
RNASEH2C deficiency, AGS3 | Mutations in RNASEH2C, encoding nuclease subunit involves in clearing cellular nucleic debris 610330 | AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, Elevated hepatic transaminases Chronic CSF lymphocytosis | 610329 |
RNASEH2A deficienc y, AGS4 | Mutations in RNASEH2A, encoding nuclease subunit involves in clearing cellular nucleic debris 606034 | AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, Elevated hepatic transaminases Chronic CSF lymphocytosis | 610333 |
SAMHD1 deficiency, AGS5 | Mutations in SAMHD1, encoding negative regulator of the immunostimulatory DNA response 606754 | AR | Not assessed | Not assessed | Induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction leading to increased CSF alpha-IFN production | Progressive encephalopathy Intracranial calcifications, Cerebral atrophy, leukodystrophy, HSMG, thrombocytopenia, anemia elevated lactates Chronic CSF lymphocytosis, Skin vascularitis, mouth ulcers, arthropathy | 612952 |
ADAR1 deficiency, AGS6 | Mutations in ADAR1, encoding a RNA-specific adenosine deaminase 146920 | AR | Not assessed | Not assessed | Catalyzes the deamination of adenosine to inosine in dsRNA substrates Markedly elevated CSF IFN-alpha | Progressive encephalopathy intracranial calcification, Severe developmental delay, leukodystrophy | 615010 |
Aicardi-Goutieres syndrome 7 (AGS7) |
IFIH1
606951 | AD | Not assessed | Not assessed | IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule | Progressive encephalopathy intracranial calcification, Severe developmental delay, leukodystrophy | 615846 |
Spondyloenchondro-dysplasia with immune dysregulation (SPENCD) | Mutations in ACP5, encoding tartrate-resitant acid phosphatase (TRAP) 171640 | AR | Not assessed | Not assessed | Upregulation of IFN-alpha and type I IFN-stimulated genes | Recurrent bacterial and viral infections, Intracranial calcification, SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia, skeletal dysplasia, short stature | 607944 |
STING--associated vasculopathy, infantile-onset |
TMEM173 encoding for STIMULATOR OF INTERFERON GENES 612374 | AR | Not assessed | Not assessed | STING activates both the NF-kappa-B and IRF3 transcription pathways to induce expression of IFN-alpha and IFN-beta and exert a potent antiviral effect | Severe infantile-onset autoinfammatory vasculopathy, | 615934 |
ADA2 deficiency | Mutations in CECR1; encoding ADA2 607575 | AR | 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 | 615688 |
Disease | Genetic defect/ Presumed pathogenesis OMIM gene | Inheritance | Affected cells | Affected function | Associated features | Phenotype OMIM number |
1) Congenital neutropenias | ||||||
Elastase deficiency (SCN1) | Mutation in ELANE: misfolded protein response, increased apoptosis 130130 | AD | N | Myeloid differentiation | Susceptibility to MDS/leukemia | 202700 |
GFI 1 deficiency (SCN2) | Mutation in GFI1: loss of repression of ELANE 600871 | AD | N | Myeloid differentiation | B/T lymphopenia | 613107 |
Kostmann Disease (SCN3) | Mutation in HAX1: control of apoptosis 605998 | AR | N | Myeloid differentiation | Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia | 610738 |
G6PC3 deficiency (SCN4) | Mutation in G6PC3: abolished enzymatic activity of glucose-6-phosphatase, aberrant glycosylation, and enhanced apoptosis of N and F 611045 | AR | N + F | Myeloid differentiation, chemotaxis, O2
− production | Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasias of trunks and limbs | 612541 |
VPS45 deficiency (SCN5) | Mutation in VPS45 controls vesicular trafficking
610035 | AR | N+F | Myeloid differentiation, migration | Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly, | 615285 |
Glycogen storage disease type 1b | Mutation in G6PT1: Glucose-6-phosphate transporter 1 602671 | AR | N + M | Myeloid differentiation, chemotaxis, O2
− production | Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly | 232220 |
Cyclic neutropenia | Mutation in ELANE: misfolded protein response 130130 | AD | N | Differentiation | Oscillations of other leukocytes and platelets | 162800 |
X-linked neutropenia/ myelodysplasia | Mutation in WAS: Regulator of actin cytoskeleton (loss of autoinhibition) 300392 | XL, gain of function | N + M | Mitosis | Monocytopenia | 300299 |
P14/LAMTOR2 deficiency | Mutation in ROBLD3/LAMTOR2: Endosomal adaptor protein 14 610389 | AR | N+L Mel | Endosome biogenesis | Neutropenia Hypogammaglobulinemia ↓CD8 cytotoxicity Partial albinism Growth failure | 610798 |
Barth Syndrome | Mutation in Tafazzin (TAZ) gene: Abnormal lipid structure of mitochondrial membrane, defective carnitine metabolism 300394 | XL | N | Myeloid differentiation | Cardiomyopathy, myopathy, growth retardation | 302060 |
Cohen syndrome | Mutation in COH1 gene: Pg unknown 607817 | AR | N | Myeloid differentiation | Retinopathy, developmental delay, facial dysmorphisms | 216550 |
Clericuzio syndrome Poikiloderma with neutropenia | Mutation in C16ORF57 (USB1), affects genomic integrity 613276 | AR | N | Myeloid differentiation | Poikiloderma, MDS | 604173 |
JAGN1 deficiency | Mutations in JAGN1, regulates secretory pathway 616012 | AR | N | Myeloid differentiation | Some with a bone phenotype | 616022 |
3-Methylglutaconic aciduria | Mutations in CLPB 616254 | AR | N | Myeloid differentiation | Microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR | Not yet assigned |
G-CSF receptor deficiency | Mutations in CSF3R, the growth factor receptor 138971 | AR | N | Myeloid differentiation | Poor response to GCSF | 162830 |
Disease | Genetic defect/ Presumed pathogenesis | Inheritance | Affected cells | Affected function | Associated features | OMIM number |
2. Defects of Motility | ||||||
Leukocyte adhesion deficiency type 1 (LAD1) | Mutation in ITGB2: B chain for adhesion proteins CD18/CD11 600065 | AR | N + M + L + NK | Adherence, Chemotaxis, Endocytosis, T/NK cytotoxicity | Delayed cord separation, skin ulcers Periodontitis Leukocytosis | 116920 |
Leukocyte adhesion deficiency type 2 (LAD2) | Mutation in SLC35C1: GDP-Fucose transporter 605881 | AR | N + M | Rolling, chemotaxis | Mild LAD type 1 features plus hh-blood group plus mental and growth retardation | 266265 |
Leukocyte adhesion deficiency type 3 (LAD3) | Mutation in KINDLIN3: Rap1-activation of β1-3 integrins 607901 | AR | N + M + L + NK | Adherence, chemotaxis | LAD type 1 plus bleeding tendency | 612840 |
Rac 2 deficiency | Mutation in RAC2: Regulation of actin cytoskeleton 602049 | AD | N | Adherence, chemotaxis O2
− production | Poor wound healing, leukocytosis | 608203 |
β-actin deficiency | Mutation in ACTB: Cytoplasmic Actin 102630 | AD | N + M | Motility | Mental retardation, short stature | 243310 |
Localized juvenile periodontitis | Mutation in FPR1: Formylated peptide receptor 136537 | AR | N | Formylpeptide induced chemotaxis | Periodontitis only | Not assigned |
Papillon-Lefèvre Syndrome | Mutation in CTSC: Cathepsin C activation of serine proteases 602365 | AR | N + M | Chemotaxis | Periodontitis, palmoplantar hyperkeratosis in some patients | 245000 |
Specific granule deficiency | Mutation in C/EBPE: myeloid transcription factor 189965 | AR | N | Chemotaxis | Neutrophils with bilobed nuclei | 245480 |
Shwachman-Diamond Syndrome | Mutation in SBDS: Defective ribosome synthesis607444 | AR | N | Chemotaxis | Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia | 260400 |
3. Defects of Respiratory Burst | ||||||
X-linked chronic granulomatous disease (CGD) | Mutation in CYBB: Electron transport protein (gp91phox) 300481 | XL | N + M | Killing (faulty O2
− production) | McLeod phenotype in patients with deletions extending into the contiguous Kell locus | 306400 |
Autosomal recessive CGD | Mutation in CYBA: Electron transport protein (p22phox) 608508 | AR | N + M | Killing (faulty O2
− production) | Infections, autoinflammatory phenotype | 233690 |
Autosomal recessive CGD | Mutation in NCF1: Adapter protein (p47phox) 608512 | AR | N + M | Killing (faulty O2
− production) | Infections, autoinflammatory phenotype | 233700 |
Autosomal recessive CGD | Mutation in NCF2: Activating protein (p67phox) 608515 | AR | N + M | Killing (faulty O2
− production) | Infections, autoinflammatory phenotype | 233710 |
Autosomal recessive CGD | Mutation in NCF4: Activating protein (p40 phox) 601488 | AR | N + M | Killing (faulty O2
− production) | Infections, autoinflammatory phenotype | 613960 |
4. Other Defects | ||||||
GATA2 deficiency (Mono MAC syndrome) | Mutations in GATA2: loss of stem cells 137295 | AD | Monocytes + peripheral DC; low NK cells | Multi lineage cytopenias | Susceptibility to Mycobacteria, papilloma viruses, histoplasmosis, alveolar proteinosis, MDS/AML/CMML | 614286 614172 |
Pulmonary alveolar proteinosis* | Mutation in CSF2RA
306250 | Biallelic mutations in pseudoautosomal gene | Alveolar macrophages | GM-CSF signaling | Alveolar proteinosis | 300770 |
Disease | Genetic defect/Presumed pathogenesis OMIM gene | Inheritance | Affected Cell | Functional Defect | Associated Features | Phenotype OMIM Number |
---|---|---|---|---|---|---|
1. Medelian Susceptibility to mycobacterial disease (MSMD) | ||||||
IL-12 and IL-23 receptor β1 chain deficiency | Mutation in IL12RB1: IL-12 and IL-23 receptor β1 chain 601604 | AR | L + NK | IFN-γ secretion | Susceptibility to Mycobacteria and Salmonella
| 614891 |
IL-12p40 deficiency | Mutation in IL12B : subunit p40 of IL12/IL23 161561 | AR | M | IFN-γ secretion | Susceptibility to Mycobacteria and Salmonella
| 614890 |
IFN-γ receptor 1 deficiency | Mutation in IFNGR1: IFN-γR ligand binding chain 107470 | AR | M + L | IFN-γ binding and signaling | Susceptibility to Mycobacteria and Salmonella
| 209950 |
IFN-γ receptor 1 deficiency | Mutation in IFNGR1: IFN-γR ligand binding chain 107470 | AD | M + L | IFN-γ binding and signaling | Susceptibility to Mycobacteria and Salmonella
| 615978 |
IFN-γ receptor 2 deficiency | Mutation in IFNGR2: IFN-γR accessory chain 147569 | AR | M + L | IFN-γ signaling | Susceptibility to Mycobacteria and Salmonella
| 614889 |
STAT1 deficiency (AD form) | Mutation in STAT1 (lost of function) 600555 | AD | M + L | IFN-γsignaling | Susceptibility to Mycobacteria, Salmonella
| 614892 |
Macrophage gp91 phox deficiency | Mutation in CYBB: Electron transport protein (gp 91 phox) 300481 | XL | Mϕ only | Killing (faulty O2
− production) | Isolated susceptibility to mycobacteria | 300645 |
IRF8-deficiency (AD form) | Mutation in IRF8: IL12 production by CD1c+ MDC 601565 | AD | CD1c + MDC | Differentiation of CD1c + MDC subgroup | Susceptibility to Mycobacteria
| 614893 |
Tyk2 deficiency | Mutation in TYK2
176941 | AR | Normal, but Multiple cytokine signaling defect | Normal | Susceptibility to intracellular bacteria (Mycobacteria, Salmonella), fungi and viruses (+/−) Elevated IgE | 611521 |
ISG15 deficiency | Mutation in ISG15
147571 | AR | IFNγ defect production | Susceptibility to Mycobacteria (BCG) Brain calcification | 616126 | |
RORc deficiency | Mutation in RORC
602943 | AR | L + NK | lack of functional RORγT protein : IFNγ defect production complete absence of IL-17A/F-producing T cells | mycobacteriosis and candidiasis | Not yet assigned |
2. Epidermodysplasia verruciformis | ||||||
EVER1 deficiency | Mutations of TMC6
605828 | AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | 226400 |
EVER2 deficiency | Mutations of TMC8
605829 | AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | 226400 |
WHIM (Warts, Hypogammaglo-bulinemia, infections, Myelokathexis) syndrome | Gain-of-function mutations of CXCR4, the receptor for CXCL12 162643 | AD | Granulocytes + Lymphocytes | Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) | warts/Human Papilloma virus (HPV) infection Neutropenia Reduced B cell number Hypogammaglobulinemia | 193670 |
4. Predisposition to severe viral infection | ||||||
STAT1 deficiency | Mutations of STAT1
600555 | AR | T and NK cells and monocytes | STAT1-dependent IFN-α, and -β response | Severe viral infections Mycobacterial infection | 613796 |
STAT2 deficiency | Mutations of STAT2
600556 | AR | T and NK cells | STAT2-dependent IFN-α, and -β response | Severe viral infections (disseminated vaccine-strain measles) | Not yet assigned |
IRF7 deficiency | Mutation in IRF7
605047 | AR | Leukocytes and plasmacytoid dendritic cells, Non-hematopoietic cells | IFN-α, and -β production IFN-λ production | Severe influenza disease | Not yet assigned |
CD16 deficiency | Mutation in CD16 146740 | AR | NK cells | Deficient spontaneous NK cell cytotoxicity | Susceptibility to severe viral infections, inc. HSV, EBV, HPV | 615707 |
5. Herpes simplex encephalitis (HSE) | ||||||
TLR3 deficiency | (b) Mutations of TLR3
603029 | AD AR | Central nervous system (CNS) resident cells and fibroblasts | TLR3-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here) | 613002 |
UNC93B1 deficiency | (a) Mutations of UNC93B1
608204 | AR | CNS resident cells and fibroblasts | UNC-93B-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis | 610551 |
TRAF3 deficiency | (c) Mutations of TRAF3
601896 | AD | CNS resident cells and fibroblasts | TRAF3-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis | 614849 |
TRIF deficiency | (c) Mutations of TRIF, also called TICAM1
607601 | AD AR | CNS resident cells and fibroblasts | TRIF-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis | 614850 |
TBK1 deficiency | (c) Mutations of TBK1
604834 | AD | CNS resident cells and fibroblasts | TBK1-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis | Not yet assigned |
6. Predisposition to invasive fungal diseases | ||||||
CARD9 deficiency | Mutations of CARD9
607212 | AR | Mononuclear phagocytes | CARD9 signaling pathway | Invasive candidiasis infection Deep dermatophytoses | 212050 |
7. Chronic mucocutaneous candidiasis (CMC) | ||||||
IL-17RA deficiency | (a) Mutations in IL17RA
605461 | AR | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RA signaling pathway | CMC Folliculitis | 613953 |
IL-17RC deficiency | Mutations in IL17RC 610925 | AR | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RC signaling pathway | CMC | Not yet assigned |
IL-17F deficiency | (b) Mutations in IL17F
606496 | AD | T cells | IL-17 F-containing dimers | CMC Folliculitis | 613956 |
STAT1 gain-of-function | (c) gain-of-function mutations in STAT1
600555 | AD | T cells, B cells, monocytes | Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells | CMC Various fungal, bacterial and viral (HSV) infections Auto-immunity (Thyroiditis, diabetes, cytopenia) Enteropathy | 614162 |
ACT1 deficiency | (c) Mutations in ACT1, also called TRAF3IP2
(607043) | AR | T cells, fibroblasts | Fibroblasts fail to respond to IL-17A and IL-17 F, and their T cells to IL-17E | CMC Blepharitis, Folliculitis and macroglossia | 615527 |
8. TLR signaling pathway deficiency | ||||||
IRAK-4 deficiency | Mutations of IRAK4, a component of TLR- and IL-1R-signaling pathway 606883 | AR | Lymphocytes + Granulocytes + Monocytes | TIR-IRAK signaling pathway | Bacterial infections (pyogens) | 607676 |
MyD88 deficiency | Mutations of MYD88, a component of the TLR and IL-1R signaling pathway 602170 | AR | Lymphocytes + Granulocytes + Monocytes | TIR-MyD88 signaling pathway | Bacterial infections (pyogens) | 612260 |
9. Isolated congenital asplenia (ICA) | Mutations in RPSA
150370 | AD | Spleen | RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome | Bacteremia (encapsulated bacteria) No spleen | 271400 |
8. Trypanosomiasis | Mutations in APOL- I 603743 | AD | APOL-I | Trypanosomiasis | Not yet assigned |
Disease | Genetic defect/ Presumed pathogenesis OMIN gene | Inheritance | Affected cells | Functional defects | Associated Features | Phenotype OMIM number |
---|---|---|---|---|---|---|
1. Defects effecting the inflammasome | ||||||
Familial Mediterranean Fever | Mutations of MEFV (lead to gain of pyrin function, resulting in inappropriate IL-1β release)
608107 | AR AD | Mature granulocytes, cytokine-activated monocytes. | Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased. | Recurrent fever, serositis and inflammation responsive to colchicine. Predisoposes to vasculitis and inflammatory bowel disease. | 249100 134610 |
Mevalonate kinase deficiency (Hyper IgD syndrome) | Mutations of MVK (lead to a block in the mevalonate pathway. Interleukin-1beta mediates the inflammatory phenotype)
251170 | AR | affecting cholesterol synthesis; pathogenesis of disease unclear | Periodic fever and leukocytosis with high IgD levels | 260920 | |
Muckle-Wells syndrome | Mutations of NLRP3 (also called NALP3 CIAS1 or PYPAF1) (lead to constitutive activation of the NLRP3 inflammasome)
606416 |
AD
| PMNs Monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing | Urticaria, SNHL, amyloidosis. | 191900 |
Familial cold autoinflammatory syndrome 1 | Mutations of NLRP3 (See above) 606416 |
AD
|
PMNs, monocytes
| same as above | Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure. | 120100 |
Familial cold autoinflammatory syndrome 2 | Mutations of NLRP12 609648 |
AD
|
PMNs, monocytes
| same as above | Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure. | 611762 |
Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) | Mutations of NLRP3 CIAS1 (See above) 606416 |
AD
|
PMNs, chondrocytes
| same as above | Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation.
| 607115 |
NLRC4-MAS (macrophage activating syndrome) Familial cold autoinflammatory syndrome 4 | Mutation in NLRC4 (see functional defect) 606831 |
AD
|
PMNs monocytes macrophages
| Gain of function mutation in NLRC4 results in elevated secretion of IL-1β and IL-18 as well as macrophage activation | Severe enterocolitis and macrophage activation syndrome | 616050 616115 |
PLAID (PLCγ2 associated antibody deficiency and immune dysregulation) Familial cold autoinflammatory syndrome 3 | Mutation in PLCG2 ((see functional defect) 600220 | AD | B cells, NK, Mast cells | Mutations cause activation of IL-1 pathways | Cold urticaria hypogammaglobulinemia | 614468 |
APLAID (autoinflammation and PLCγ2 associated antibody deficiency and immune dysregulation) | Mutation (c2120C > A) in PLCG2 (see function defect) 600220 | AD | B cells, NK, mast cells | The mutation leads to activation of the NLRP3 inflammasome (not provoked by cold temperature) | Blistering skin lesion, pulmonary and bowel disease | 614878 |
2. Non inflammasome-related conditions | ||||||
(TNF receptor-associated periodic syndrome (TRAPS) | Mutations of TNFRSF1A (resulting in increased TNF inflammatory signaling) 191190 | AD | PMNs, monocytes | Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF | Recurrent fever, serositis, rash, and ocular or joint inflammation | 142680 |
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome | Mutations of PSTPIP1 (also called C2BP1) (affects both pyrin and protein tyrosine phosphatase to regulate innate and adaptive immune responses) 606347 | AD | Hematopoietic tissues, upregulated in activated T-cells | Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response | Destructive arthritis, inflammatory skin rash, myositis | 604416 |
Blau syndrome | Mutations of NOD2 (also called CARD15) (involved in various inflammatory processes) 605956 | AD | Monocytes | Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling | Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30 % develop Crohn’s disease | 186580 |
ADAM17 deletion | Mutation in ADAM17 (leads to tumor necrosis factor α converting enzyme deficiency) 603639 | AR | Leukocytes and epithelial cells | Defective TNFα production | Early onset diarrhea and skin lesions | 614328 |
Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) | Mutations of LPIN2 (increased expression of the proinflammatory genes) 605519 | AR | Neutrophils, bone marrow cells | undefined | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders | 609628 |
DIRA (Deficiency of the Interleukin 1 Receptor Antagonist) | Mutations of IL1RN (see functional defect) 147679 | AR | PMNs, Monocytes | Mutations in the IL1 receptor antagonist allow unopposed action of Interleukin 1 | Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis. | 612852 |
DITRA – Deficiency of IL-36 receptor antagonist | Mutation in IL36RN (see functional defect) 605507 | AR | Keratinocyte Leukocytes | Mutations in IL-36RN leads to increase IL-8 production | Pustular Psoriasis | 614204 |
SLC29A3 mutation | Mutation in SLC29A3
612373 | AR | Leukocyte, bone cells | Hyperpigmentation hypertrichosis | Histiocytosis-lymphadenopathy plus syndrome | 602782 |
CAMPS (CARD14 mediated psoriasis) | Mutation in CARD14 (see functional defect) 607211 | AD | Mainly in Keratinocyte | Mutations in CARD14 activate the NF-kB pathway and production of IL-8 | Psoriasis | 602723 |
Cherubism | Mutation in SH3BP2 (see functional defect) 602104 | AD | Stroma cells, bone cells | Hyperactived macrophage and increase NF-kB | Bone degeneration in jaws | 118400 |
CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) | Mutation in PSMB8, (see functional defect) 177046 | AR | Keratinocyte, B cell adipose cells | Mutations cause increase IL-6 production | Dystrophy, panniculitis | 256040 |
COPA defect | Mutation in COPA (Coatamer protein complex, subunit alpha) | AD | PMNs and tissues specific cells | Mutant COPA leads to defective intracellular transport via the coat protein complex I (COPI) | Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production | 601924 |
Disease | Genetic defect; presumed pathogenesis OMIM gene | Inheritance | Laboratory features | Associated Features | Phenotype OMIM number |
---|---|---|---|---|---|
1) Integral complement cascade component deficiencies | |||||
C1q deficiency |
C1QA,: Classical complement pathway component 120550 | AR | Absent CH50 hemolytic activity, Defective activation of the classical pathway Diminished clearance of apoptotic cells | SLE, infections with encapsulated organisms | 613652 |
C1q deficiency |
C1QB: Classical complement pathway component 120570 | AR | Absent CH50 hemolytic activity, Defective activation of the classical pathway Diminished clearance of apoptotic cells | SLE, infections with encapsulated organisms | 613652 |
C1q deficiency |
C1QC: Classical complement pathway component 120575 | AR | Absent CH50 hemolytic activity, Defective activation of the classical pathway Diminished clearance of apoptotic cells | SLE, infections with encapsulated organisms | 613652 |
C1r deficiency |
C1R: Classical complement pathway component 613785 | AR | Absent CH50 hemolytic activity, Defective activation of the classical pathway | SLE, infections with encapsulated organisms | 216950 |
C1s deficiency |
C1S: Classical complement pathway component 120580 | AR | Absent CH50 hemolytic activity Defective activation of the classical pathway | SLE, infections with encapsulated organisms | 613783 |
C4 deficiency |
C4A, Classical complement pathway components 120810 | AR | 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 | 614380 |
C4 deficiency |
C4B: Classical complement pathway components 120820 | AR | 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 | 614379 |
C2 deficiency |
C2: Classical complement pathway component 217000 | AR | Absent CH50 hemolytic activity, Defective activation of the classical pathway | SLE, infections with encapsulated organisms, atherosclerosis | 613927 |
C3 deficiency LOF |
C3: Central complement component 120700 | AR | Absent CH50 and AH50 hemolytic activity Defective opsonization Defective humoral immune response | Infections; glomerulonephritis; Atypical Hemolytic-uremic syndrome with gain-of-function mutations. | 613779 |
C3 GOF |
C3: Central complement component 120700 | Gain-of-function AD | Increased activation of complement | Atypical Hemolytic-uremic syndrome | 612925 |
C5 deficiency |
C5: Terminal complement component 120900 | AR | Absent CH50 and AH50 hemolytic activity Defective bactericidal activity | Neisserial infections | 609536 |
C6 deficiency |
C6: Terminal complement component 217050 | AR | Absent CH50 and AH50 hemolytic activity Defective bactericidal activity | Neisserial infections | 612446 |
C7 deficiency |
C7: Terminal complement component 217070 | AR | Absent CH50 and AH50 hemolytic activity Defective bactericidal activity | Neisserial infections | 610102 |
C8 αdeficiency |
C8A: Terminal complement component 120950 | AR | Absent CH50 and AH50 hemolytic activity Defective bactericidal activity | Neisserial infections | 613790 |
C8γ deficiency |
C8G: Terminal complement component 120930 | AR | Absent CH50 and AH50 hemolytic activity Defective bactericidal activity | Neisserial infections | 613790 |
C8β deficiency |
C8B: Terminal complement component 120960 | AR | Absent CH50 and AH50 hemolytic activity Defective bactericidal activity | Neisserial infections | 613789 |
C9 deficiency |
C9: Terminal complement component 120940 | AR | Reduced CH50 and AP50 hemolytic activity Deficient bactericidal activity | Mild susceptibility to Neisserial infections | 613825 |
MASP2 deficiency |
MASP2: Cleavage of C4 605102 | AR | Deficient activation of the lectin activation pathway | Pyogenic infections; Inflammatory lung disease, autoimmunity | 613791 |
Ficolin 3 deficiency |
FCN3: Activates the classical complement pathway 604973 | AR | Absence of complement activation by the Ficolin 3 pathway. | Respiratory infections, abscesses | 613860 |
2) Complement Regulatory defects | |||||
C1 inhibitor deficiency |
SERPING1: regulation of kinins and complement activation 606860 | AD | 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 | 106100 |
Factor B |
CFB: Activation of the alternative pathway 138470 | AD | Gain-of-function mutation with increased spontaneous AH50 | aHUS | 612924 |
Factor D deficiency |
CFD: Regulation of the alternative complement pathway 134350 | AR | Absent AH50 hemolytic activity | Neisserial infections | 613912 |
Properdin deficiency |
CFP: Regulation of the alternative complement pathway 300383 | XL | Absent AH50 hemolytic activity | Neisserial infections | 312060 |
Factor I deficiency |
CFI: Regulation of the alternative complement pathway 217030 | AR | Spontaneous activation of the alternative complement pathway with consumption of C3 | Infections, Neisserial infections, aHUS, preeclampsia | 610984 612923 |
Factor H deficiency |
CFH: Regulation of the alternative complement pathway 134370 | AR/AD | Spontaneous activation of the alternative complement pathway with consumption of C3 | Infections, Neisserial infections, aHUS, preeclampsia | 609814 235400 |
Factor H –related protein deficiencies |
CFHR1-5: Bind C3b 134371 600889 605336 605337 608593 | AR/AD | Normal CH50, AH50, autoantibodies to Factor H. Linked deletions of one or more CFHR genes leads to susceptibility autoantibody-mediated aHUS | aHUS, Neisserial infections | 235400 |
Thrombomodulin |
THBD: Regulates complement and coagulant activation 188040 | AD | Normal CH50, AH50 | aHUS | 612926 |
Complement Receptor 3 (CR3) deficiency |
ITGAM
120980 | AR | CR3 expression is lost in LAD1. See LAD1 in Table 5
| Infections | 609939 |
Membrane Cofactor Protein (CD46) deficiency |
CD46: Dissociates C3b and C4b 120920 | AD | Inhibitor of complement alternate pathway, decreased C3b binding | aHUS, infections, preeclampsia | 612922 |
Membrane Attack Complex Inhibitor (CD59) deficiency |
CD59: Regulates the membrane attack complex formation 107271 | AR | Erythrocytes highly susceptible to complement-mediated lysis | Hemolytic anemia, polyneuropathy | 612300 |
Disease | Genetic defect/presumed pathogenesis | Circulating T cells | Circulating B cells | Serum Ig | Associated features/similar PID |
---|---|---|---|---|---|
Associated with somatic mutations | |||||
Autoimmune lymphoproliferative syndrome (ALPS–SFAS) | Somatic mutation in TNFRSF6
| Increased CD4−CD8−double negative (DN) T alpha/beta cells | Normal, but increased number of CD5+ B cells | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias Defective lymphocyte apoptosis/ALPS–FAS (=ALPS type Im)
|
RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in KRAS (gain-of-function) | 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 (gain-of-function) | Increased CD4−CD8−double negative (DN) T alpha/beta cells | Lymphocytosis | Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like
| |
Cryopyrinopathy, (Muckle-Wells /CINCA/NOMID-like syndrome) | Somatic mutation in NLRP3
| Normal | Normal | Normal | Urticaria-like rash, arthropathy, neurological symptoms |
Associated with autoantibodies | |||||
Chronic mucocutaneous candidiasis (isolated or with APECED syndrome) | Germline mutation in AIRE AutoAb to IL-17 and/or IL-22 | Normal | Normal | Normal | Endocrinopathy, chronic mucocutaneous candidiasis/CMC
|
Adult-onset immunodeficiency | AutoAb to IFN gamma | Decreased naive T cells | Normal | Normal | Mycobacterial, fungal, Salmonella VZV infections/MSMD, or CID
|
Recurrent skin infection | AutoAb to IL-6 | Normal | Normal | Normal | Staphylococcal infections/STAT3 deficiency
|
Pulmonary alveolar proteinosis | AutoAb to GM-CSF | Normal | Normal | Normal | Pulmonary alveolar proteinosis, cryptococcal meningitis/CSF2RA deficiency
|
Acquired angioedema | AutoAb to CI inhibitor | Normal | Normal | Normal | Angioedema/C1 INH deficiency (hereditary angioedema) |
Atypical Hemolytic Uremic Syndrome | AutoAb to Complement Factor H | Normal | Normal | Normal | aHUS Spontaneous activation of the alternative complement pathway |