Genes associated with monogenic forms of CVID: summary of genetic, clinical and immunological features
| Gene, OMIM number | Number of publ. patients | Effect on protein | Inheritance | Onset | Clinical spectrum | Immunological spectrum | CVID or separate entity | Ref |
|---|---|---|---|---|---|---|---|---|
| Genes encoding receptors and ligands | ||||||||
| ICOS, *604558 | 15 (7 fam.) | LOF (absent expr.) | AR | Infancy to adulthood | RTI, GI infections, opportunistic infections, bacterial skin infections, localised herpes simplex infections, neuroborreliosis, bronchiectasis, AI (incl. AI cytopenia, rheumatic disease, IBD), BLH, splenomegaly, hepatomegaly, granulomata, malignancy. | ↓ IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ antibody responses to protein and/or polysaccharide vaccines, ↓ or nl total B cells, ↓↓ or absent memory B cells, absent bone marrow plasma cells, nl total/CD4+/ CD8+ T cells, ↓ or nl CD4+ and CD8+ memory T cells, nl Treg cells, ↓ or nl circulating Tfh cells, ↓ or nl production of Th1/Th2/Th17 cytokines, ↓ CTLA-4 expr, nl CD40(L) expr. | ICOS deficiency | 5 10–14 |
| TNFRSF13B (TACI), *604907 | 2147 | LOF (usually nl expr.) | Monoallelic/ biallelic | Early childhood to adulthood | RTI, GI infections, bronchiectasis, AI (incl. AI cytopenia, rheumatic disease, IBD), BLH, splenomegaly (± splenectomy), granulomata, malignancy. Note: variants also found in asymptomatic individuals and in patients with sIgAD or IgG subclass deficiency. | ↓ IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ antibody responses to polysaccharide vaccines, ↓ or nl or ↑ total B cells, ↓ or nl memory B cells, ↓ or nl total/CD4+/ CD8+ T cells, ↓ or nl CD4+ and CD8+ naive/memory T cells, ↓ or nl Treg cells. | CVID, disease-predisposing | 6 7 18–21 23–30 |
| TNFRSF13C (BAFF-R), *606269 | >80 | LOF/GOF (usually nl expr.) | Monoallelic/biallelic | Infancy to late adulthood | RTI, GI infections, cholangitis, sacroiliitis, bronchiectasis, AI (incl. AI cytopenia, IBD), BLH, splenomegaly, granulomata, chronic diarrhoea with weight loss, failure to thrive. Note: variants also found in asymptomatic individuals and in patients with sIgAD or isolated IgM deficiency. | ↓ IgG, nl to undetectable IgM, nl to undetectable IgA, ↓ antibody responses to polysaccharide vaccines, nl to absent total B cells, nl or ↑ transitional B cells, nl or ↓ memory B cells, nl total T cells, nl T cell subsets. | CVID, disease-predisposing | 8 22 25 31–35† |
| TNFSF12 (TWEAK), *602695 | 3 (1 fam.) | LOF (nl expr.) | AD | Infancy | RTI, pneumococcal meningitis, osteomyelitis, AI thrombocytopenia and neutropenia, warts. | ↓ IgG or low nl IgG with ↓↓ IgG2, ↓ IgM, ↓ IgA, ↓ antibody responses to protein and polysaccharide vaccines, ↓ or nl total B cells, ↓ memory B cells, ↑ naive B cells, nl or ↑ total T cells, nl total CD4+ T cells, ↑ total CD8+ T cells, ↑ double negative T cells, ↓↓ in vitro apoptotic function. | CVID | 37 |
| CD19, *107265 | 10 (7 fam.) | LOF (↓ or absent expr.) | AR | Infancy to early childhood | RTI, GI infections, bacterial conjunctivitis (± dacryocystitis), bacterial skin infections, bronchiectasis, intermittent microscopic haematuria, postinfectious glomerulonephritis, IgA nephropathy. | ↓ IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ antibody responses to protein and polysaccharide vaccines, nl total CD20+ B cells, ↓↓ memory B cells, ↓↓ BCR signalling, nl CD81 expr., ↓ CD21 expr., nl total T cells, nl T cell subsets. | CVID | 38 41–46 |
| CD81, *186845 | 1 | LOF (absent expr.) | AR | Infancy | RTI, AI thrombocytopenia, severe glomerulonephritis with progression to end-stage renal disease, undefined systemic inflammatory syndrome. | ↓ IgG, nl IgM, ↓ to low nl IgA, ↓ antibody responses to protein and polysaccharide vaccines, nl total CD20+ B cells, ↓↓ memory B cells, ↓↓ BCR signalling, absent CD19 expr., ↓ CD21 expr., nl total T cells, nl T cell subsets. | CVID | 39 |
| CR2 (CD21), *120650 | 2 (2 fam.) | LOF (absent expr.) | AR | Early childhood to childhood | RTI, chronic diarrhoea with weight loss, splenomegaly, myalgia, rigidity. | ↓ IgG, ↓ or nl IgM, ↓ IgA, ↓ antibody response to polysaccharide vaccines, nl total CD19+ B cells, ↓ memory B cells, mildly ↓ BCR signalling, nl CD19/CD81 expr., nl total T cells, nl T cell subsets. | CVID | 40 49 |
| MS4A1 (CD20), *112210 | 1 | LOF (absent expr.) | AR | Infancy | RTI | ↓ IgG, nl IgM, nl IgA, ↓ antibody responses to polysaccharide vaccines, nl total B cells, ↓↓ memory B cells, nl total T cells, nl T cell subsets. | CVID | 50 |
| TNFRSF7 (CD27), *186711 | 17 (9 fam.) | LOF (↓ or absent expr.) | AR | Infancy to childhood | Chronic EBV viraemia, severe/atypical EBV-associated infections (eg, severe mononucleosis, pneumonia, meningitis/encephalitis, oral/perianal ulcers, uveitis), EBV-induced lymphoproliferation (eg, BLH, splenomegaly, hepatomegaly, lymphocytic infiltration of non-lymphoid organs, HLH, lymphoma), RTI, bronchiectasis, bacterial skin infections, giardiasis, fulminant bacterial sepsis. | ↓ or nl or ↑ IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ or nl antibody responses to protein and/or polysaccharide vaccines, ↓ or nl total B cells, absent memory B cells, nl or ↑ transitional B cells, nl or ↑ CD21low B cells, ↓ or nl CD4+ T cells, nl or ↑ CD8+ T cells, ↓ or nl CD8+ memory T cells, ↓ or nl in vitro T cell proliferation responses, ↓ or nl or ↑ NK cells, ↓ or nl NK cell cytotoxicity, ↓ or nl iNKT cells. | CD27 deficiency | 51–53 |
| IL21, *605384 | 1 | LOF (nl expr.) | AR | Infancy | RTI, early onset IBD, failure to thrive, recurrent oral aphthous ulcers. | ↓ IgG, nl IgM, nl IgA, ↑ IgE, ↓ antibody responses to protein and polysaccharide vaccines, ↓ total B cells, ↓↓ memory B cells, ↓ naive B cells, ↑ transitional B cells, nl total/CD4+/CD8+ T cells, ↓ in vitro T cell proliferation responses. | IL-21 deficiency | 55 |
| IL21R, *605383 | 8 (6 fam.) | LOF (↓ or absent expr.) | AR | Infancy to early childhood | RTI, GI infections, opportunistic infections (including cryptosporidiosis with progression to end-stage biliary/liver disease), pulmonary tuberculosis, bronchiectasis, BLH, hepatosplenomegaly, discoid lupus/chronic inflammatory skin disease, failure to thrive. | ↓ or nl IgG, nl or ↑ IgM, ↓ or nl IgA, nl or ↑ IgE, ↓ antibody responses to protein and/or polysaccharide vaccines, ↓ or nl or ↑ total B cells, ↓ or nl memory B cells, nl or ↑ transitional B cells, nl total T cells, ↓ or nl CD4+ T cells, ↓ or nl CD8+ T cells, ↓ or nl Tfh cells, ↓ or nl in vitro B and T cell proliferation responses, ↓ or nl production of Th cytokines, ↓ or nl NK cells, ↓ or nl NK cell cytotoxicity. | IL-21R deficiency | 54 56–58 |
| LRBA, *606453 | >50 | LOF (majority ↓ or absent expr.) | AR | Infancy to childhood | Severe AI (incl. AI cytopenia, severe IBD, type 1 diabetes mellitus), severe (EBV-induced) lymphoproliferation with generalised BLH and lymphocytic infiltration of organs (eg, kidney, brain), LIP, GLILD, granulomata, chronic lung disease, bronchiectasis, splenomegaly, hepatomegaly, malignancy, finger clubbing, failure to thrive, RTI, GI infections, opportunistic infections, bacterial skin infections, deep abscesses, bacterial conjunctivitis, warts, mollusca contagiosa, food allergy, allergic dermatitis, urticaria, growth hormone deficiency. | ↓ or nl or ↑ IgG, ↓ or nl IgM, ↓ or nl or ↑ IgA, ↓ or nl antibody responses to protein and/or polysaccharide vaccines, ↓ or nl total B cells, ↓ or nl memory B cells, ↓ or nl plasmablasts, ↓ or nl or ↑ transitional B cells, ↓ or nl or ↑ naive B cells, nl or ↑ CD21low B cells, ↓ B cell proliferation and Ig secretion, ↓ or nl total lymphocytes, ↓ or nl or ↑ total/CD4+/CD8+ T cells, nl or ↑ CD4+/CD8+ memory T cells, ↓ or nl CD4+/CD8+ naive T cells, ↓ or nl Treg cells, nl or ↑ double negative T cells, nl or ↑ Tfh cells, ↓ or nl in vitro T cell proliferation responses, ↓ or nl Fas-mediated apoptosis, ↓ CTLA-4 surface expr., ↑ sCD25, ↓ or nl NK cells, ↓ or nl neutrophils. | LRBA deficiency | 59 62–72 |
| CTLA4, *123890 | 23 (12 fam.) | LOF (usually ↓ expr.) | AD | Infancy to adulthood | Severe AI (incl. AI cytopenia, severe IBD, type 1 diabetes mellitus), severe (EBV-induced) lymphoproliferation with generalised BLH and lymphocytic infiltration of organs (eg, kidney, brain, bone marrow), GLILD, granulomata, bronchiectasis, splenomegaly, hepatomegaly, malignancy, failure to thrive, RTI, GI infections, opportunistic infections, pulmonary tuberculosis, warts, food allergy, allergic dermatitis. Note: variants also found in asymptomatic individuals. | ↓ or nl IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ or nl antibody responses to polysaccharide vaccines, ↓ or nl total B cells, ↓ or nl memory B cells, nl or ↑ CD21low B cells, ↓ or nl total lymphocytes, ↓ or nl total T cells, ↓ or nl CD4+/CD8+ T cells, ↓ or nl CD4+/CD8+ naive T cells, nl or ↑ double negative T cells, nl or ↑ Treg cells, ↓ FoxP3/CD25 expr. on Treg cells, ↓ suppressive activity Treg cells, ↑ activity effector T cells, ↓ or nl NK cells, ↓ or nl NKT cells. | CTLA-4 deficiency | 60 61 73 74 |
| Genes encoding intracellular signalling molecules | ||||||||
| PRKCD, *176977 | 6 (4 fam.) | LOF (↓ or absent expr.) | AR | Infancy to early childhood | Severe systemic AI with features reminiscent of systemic lupus erythematosus, severe (EBV/CMV-induced) lymphoproliferation with generalised BLH, splenomegaly, hepatomegaly, RTI, GI infections, urinary tract infections, failure to thrive. | ↓ or nl IgG, nl or ↑ IgM, nl or ↑ IgA, ↓ or nl antibody responses to protein and/or polysaccharide vaccines, ↓ or nl or ↑ total B cells, ↓ memory B cells, nl or ↑ transitional B cells, nl or ↑ naive B cells, ↑ CD21low B cells, ↓ or nl total/CD4+/CD8+ T cells, nl or ↑ double negative T cells, mildly ↓ or nl in vitro T cell proliferation responses, ↓ or nl NK cells, ↓ or nl NK cell cytotoxicity, nl NKT cells, ↓ or nl neutrophil microbial killing capacity. | PKCδ deficiency | 75 80–82 |
| PLCG2, *600220 | 30 (4 fam.) | GOF (usually nl expr.) | AD | Infancy to childhood | Cold urticaria (negative ice cube skin test, positive evaporative cooling skin test), atopy (food, airway, skin), skin granulomata, blistering skin lesions, RTI, onychomycosis, varicella zoster infections, bacterial skin infections, AI (mainly involving skin and thyroid gland). | ↓ or nl IgG, ↓ or nl IgM, ↓ or nl IgA, nl or ↑ IgE, ↓ or nl antibody responses to polysaccharide vaccines, nl total B cells, ↓ or nl memory B cells, ↓ BCR signalling, ↓ in vitro B cell proliferation responses, negative cold agglutinins and cryoglobulins, positive antinuclear antibodies, nl total T cells, nl T cell subsets, ↓ or nl NK cells, ↓ or nl NKT cells. | PLAID | 83 84 |
| NFKB2, *164012 | 17 (10 fam.) | LOF (↓ or nl expr.) | AD | Infancy to childhood | RTI, GI infections, localised herpes simplex infections, onychomycosis, bronchiectasis, pituitary hormone deficiencies (mainly ACTH deficiency), AI (mainly involving skin, hair and nails). | ↓ or nl IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ or nl antibody responses to protein and/or polysaccharide vaccines, absent or ↓ or nl B cells, ↓ or nl memory B cells, nl or ↑ total T cells, nl CD4+/CD8+ T cells, ↓ or nl CD4+/CD8+ memory T cells, nl or ↑ recent thymic emigrant CD4+ T cells, ↓ or nl Tfh cells, ↓ or nl Treg cells, ↓ or nl in vitro T cell proliferation responses, ↓ or nl NK cells, ↓ or nl NK cell cytotoxicity. | NF-κB2 deficiency | 85 87–91 |
| NFKB1, *164011 | 18 (3 fam.) | LOF (↓ expr.) | AD | Early childhood to adulthood | RTI, GI infections, bacterial skin infections, AI (mainly involving blood cells, gut, hair and thyroid gland), pyoderma gangrenosum, bronchiectasis, chronic lung disease, LIP, BLH, splenomegaly, hepatomegaly, malignancy. Note: variants also found in asymptomatic individuals and in patients with other antibody deficiencies (eg, IgG subclass deficiency). | Full immunological phenotype not reported. ↓ or nl IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ or nl antibody responses to protein and/or polysaccharide vaccines, nl total B cells, nl total T cells. | NF-κB1 deficiency | 86 |
| PIK3CD, *602839 | > 50 | GOF (usually nl expr.) | AD | Infancy to early childhood | RTI, GI infections, bacterial skin infections, deep abscesses, warts, persistent CMV/EBV viraemia, failure to thrive, bronchiectasis, AI (AI cytopenia, IBD, AI primary sclerosing cholangitis), (EBV/CMV-induced) lymphoproliferation with (generalised) BLH, splenomegaly, hepatomegaly, malignancy (mainly lymphoma). | ↓ or nl or ↑ IgG, ↓ or nl IgG2, ↓ or nl IgA, ↓ or nl or ↑ IgM, ↓ or nl antibody responses to protein and/or polysaccharide vaccines, ↓ or nl total B cells, absent or ↓ or nl memory B cells, nl or ↑ transitional B cells, ↓ or nl naive B cells, ↓ or nl total lymphocytes, ↓ or nl total/CD4+/CD8+ T cells, nl or ↑ CD4+/CD8+ memory T cells, ↓ or nl CD4+/CD8+ naive T cells, nl Treg cells, ↑ T cell activation-induced cell death, ↓ or nl or ↑ NK cells, ↓ or nl or ↑ NKT cells, ↓ or nl NK cell cytotoxicity. | APDS | 76 77 92–97 |
| PIK3R1, *171833 | 12 (9 fam.) | LOF (nl expr.) | AD | Infancy to childhood | RTI, GI infections, bacterial conjunctivitis, persistent CMV/EBV viraemia, failure to thrive, bronchiectasis, AI (AI cytopenia, IBD, rheumatic disease), (EBV/CMV-induced) lymphoproliferation with (generalised) BLH, splenomegaly (± splenectomy), hepatomegaly, malignancy (mainly lymphoma). | Full immunological phenotype not reported in ref 100. ↓ or nl IgG, ↓ or nl or ↑ IgM, ↓ IgA, ↓ antibody responses to polysaccharide vaccines, ↓ or nl total B cells, ↓ or nl memory B cells, nl or ↑ transitional B cells, nl or ↑ total T cells, ↓ or nl CD4+ (total/naive/memory) T cells, ↓ or nl or ↑ CD8+ (total/naive/memory) T cells, nl or ↑ Treg cells, nl double negative T cells, ↓ Th17 cells, ↓ or nl NK cells. | APDS-like | 98–101 |
| VAV1, *164875 | 1 | LOF (↓ expr.) | AD | Adulthood | Full clinical phenotype not reported. RTI, GI infections, genitourinary infections, bronchiectasis. | Full immunological phenotype not reported. ↓ IgG, absent IgM/IgA, nl total B cells, nl total T cells, ↓ CD4+ T cells, nl CD8+ T cells, ↓ in vitro T cell proliferation responses to mitogens. | Vav1 deficiency | 103 |
| RAC2, *602049 | 2 (1 fam.) | LOF (absent expr.) | AR | Infancy to childhood | RTI, failure to thrive, bronchiectasis, arthralgia, AI endocrinopathy, BLH, poststreptococcal glomerulonephritis (±progression to end-stage renal disease), solar urticaria, food allergy, coagulopathy. | ↓ IgG, ↓ IgM, ↓ IgA, ↓ antibody responses to polysaccharide vaccines, ↓↓ total B cells, nl total/CD4+/CD8+ T cells, ↓ CD4+ and CD8+ naive T cells, ↓ recent thymic emigrant CD4+ T cells, ↓ Treg cells, ↓ TRECs, ↓ KRECs, nl neutrophils, ↓ neutrophil chemotaxis, ↓ and aberrant morphology of neutrophil granules. | RAC2 deficiency | 104 |
| BLK, *191305 | 2 (1 fam.) | LOF (nl expr.) | AD | Infancy | RTI, bacterial skin infections. | ↓ IgG, ↓ or nl IgA, ↓ or nl IgM, ↓ antibody responses to polysaccharide vaccines, ↓ or nl total B cells, nl total T cells. | CVID | 105 |
| IKZF1, *603023 | 21 (6 fam.) | LOF (↓ or nl expr.) | AD | Early childhood to late adulthood | RTI, Streptococcus pneumoniae infections, GI infections, bacterial skin infections, apthous ulcers, AI (AI cytopenia), malignancy (acute lymphoblastic leukaemia). Note: variants also found in asymptomatic individuals. | ↓ IgG, ↓ or nl IgM, ↓ or nl IgA, ↓ or nl antibody responses to protein and/or polysaccharide vaccines, ↓↓ or ↓ or nl total B cells, ↓ or nl memory B cells, nl or ↑ total T cells, ↓ or nl or ↑ CD4+ T cells, nl or ↑ CD8+ T cells, nl in vitro T cell proliferation responses, nl Fas-mediated apoptosis, ↓ or nl or ↑ NK cells. | CVID | 78† |
| IRF2BP2, *615332 | 3 (1 fam.) | GOF (↑ expr.) | AD | Early childhood to childhood | RTI, AI (IBD, type 1 diabetes mellitus, psoriasis). | ↓ IgG, ↓ IgG2, ↓ to undetectable IgM, undetectable IgA, ↓ antibody responses to protein and/or polysaccharide vaccines, nl total B cells, ↓↓ or ↓ memory B cells, nl total/CD4+/CD8+ T cells, ↓ or nl NK cells. | CVID | 79 |
Disease onset: infancy (0–2 years), early childhood (3–8 years), childhood (9–17 years), adulthood (18–50 years), late adulthood (>50 years).
†Unpublished cases from our cohort.
↓, decreased; ↑, increased; ±, with or without; ACTH, adrenocorticotropic hormone; AD, autosomal dominant; AI, autoimmun(e)(ity); APDS, activated PI3 kinase δ syndrome; AR, autosomal recessive; BCR, B cell receptor; BLH, benign lymphoid hyperplasia; CMV, cytomegalovirus; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; CVID, common variable immunodeficiency; EBV, Epstein–Barr virus; expr., expression; fam., families; GI, gastrointestinal; GLILD, granulomatous lymphocytic interstitial lung disease; GOF, gain-of-function; HLH, hemophagocytic lymphohistiocytosis; iNKT, invariant natural killer T; IBD, inflammatory bowel disease; ICOS, inducible T cell costimulator; KRECs, κ-deleting recombination excision circles; LRBA, lipopolysaccharide-responsive beige-like anchor protein; LIP, lymphoid interstitial pneumonia; LOF, loss-of-function; nl, normal; NFKB, nuclear factor of kappa light chain enhancer of activated B cells; OMIM, Online Mendelian Inheritance in Man; PKCδ, protein kinase C delta; PLAID, PLCγ2-associated antibody deficiency and immune dysregulation; PLCγ2, phospholipase C gamma 2; publ., published; ref: references; RTI, respiratory tract infections; sIgAD, selective IgA deficiency; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; Tfh, follicular helper T (CD4+CD45RO+CXCR5+); Th, T helper (CD4+); TRECs, T cell receptor excision circles; Treg, regulatory T (CD4+CD25+FoxP3+).