Monogenetic defects associated with common variable immune deficiency
| Defect . | Gene . | Inheritance . | Laboratory findings . | Clinical findings . |
|---|---|---|---|---|
| BAFF receptor deficiency | TNFRSF13C (BAFF-R) | AR | Low IgG and IgM, normal IgA | Not fully penetrant, infection only |
| TWEAK deficiency | TWEAK (TNFSF12) | AD | Low IgM and A, lack of antipneumococcal antibody | Pneumonia, bacterial infections, warts, thrombocytopenia; neutropenia |
| ICOS | ICOS | AR | Low IgG and IgA and/or IgM | Fully penetrant, mostly bacterial infection, some lymphoproliferation and autoimmunity, combined immunodeficiency possible |
| Severe loss of class-switched memory | ||||
| TACI deficiency | TNFRSF13B (TACI) | AD or AR | Low IgG and IgA and/or IgM | Not fully penetrant, bacterial infections, autoimmunity, and lymphoproliferation |
| CD19 deficiency | CD19 | AR | Low IgG and IgA and/or IgM | Recurrent infections, may have IgA nephropathy |
| CD81 deficiency | CD81 | AR | Low IgG, low or normal IgA and IgM | Recurrent infections, glomerulonephritis, Henoch-Schönlein purpura |
| CD20 deficiency | CD20 | AR | Low IgG, normal or elevated IgM and IgA | Recurrent infections |
| CD21 deficiency | CR2 | AR | Low IgG, impaired antipneumococcal response | Recurrent infections |
| CD27 | CD27 | AR | Hypogammaglobulinemia | Recurrent infections; persistent EBV viremia |
| PIK3CD mutation (GOF) | PIK3CD GOF | AD | All isotypes decreased | Severe bacterial infections; decreased or absent pro-B cells, herpesvirus and EBV disease |
| NFKB1 deficiency | NFKB1 | AD | Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells | About 70% penetrant, recurrent sinopulmonary infections, EBV proliferation, autoimmune cytopenias, enteropathy, interstitial lung disease, aphthous lesions |
| NFKB2 deficiency | NFKB2 | AD | Low serum IgG, IgA, and IgM; low B-cell numbers | Recurrent sinopulmonary infections, alopecia, and autoimmune endocrinopathies |
| IKAROS deficiency | IKZF1 | AD | Low IgG and IgA and/or IgM; reduced B-cell numbers | Recurrent infections, ALL, some with autoimmunity |
| IL21 deficiency | IL21 | AR | Impaired B-cell differentiation | Inflammatory bowel disease, infections |
| IL21R deficiency | IL21R | AR | Low IgG, defective class-switched B cells, and defective antibody responses | Recurrent infections, cryptosporidial liver disease |
| LRBA deficiency | LRBA | AR | Hypogammaglobulinemia, low IgG and IgA defective class-switched B cells, expanded CD21low B cells | Chronic interstitial lung disease; autoimmunity; inflammatory bowel disease; endocrinopathy; infections |
| CTLA4 deficiency | CTLA4 | AD | Hypogammaglobulinemia, low IgG and IgA; sometimes IgM, defective class-switched B cells, expanded CD21low B cells | Not fully penetrant, mainly autoimmunity and inflammatory organ disease, infections, Hodgkin lymphoma |
| PIK3CD deficiency | PIK3CD | AD, AR | Hypogammaglobulinemia, increased IgM, defective class-switched B cells, expanded CD21low B cells, expanded CD57+ CD8 T cells | Recurrent infections, lymphoproliferation; autoimmunity, B-cell lymphoma |
| PIK3R1 deficiency | PIK3R1 | AD; AR | Hypogammaglobulinemia, increased IgM, defective class-switched B cells, expanded CD21low B cells | Recurrent infections, lymphoproliferation; B-cell lymphoma; neurodevelopmental delay |
| IRF2BP2 deficiency | IRF2BP2 | AD | Hypogammaglobulinemia | Recurrent infections, colitis |
| Defect . | Gene . | Inheritance . | Laboratory findings . | Clinical findings . |
|---|---|---|---|---|
| BAFF receptor deficiency | TNFRSF13C (BAFF-R) | AR | Low IgG and IgM, normal IgA | Not fully penetrant, infection only |
| TWEAK deficiency | TWEAK (TNFSF12) | AD | Low IgM and A, lack of antipneumococcal antibody | Pneumonia, bacterial infections, warts, thrombocytopenia; neutropenia |
| ICOS | ICOS | AR | Low IgG and IgA and/or IgM | Fully penetrant, mostly bacterial infection, some lymphoproliferation and autoimmunity, combined immunodeficiency possible |
| Severe loss of class-switched memory | ||||
| TACI deficiency | TNFRSF13B (TACI) | AD or AR | Low IgG and IgA and/or IgM | Not fully penetrant, bacterial infections, autoimmunity, and lymphoproliferation |
| CD19 deficiency | CD19 | AR | Low IgG and IgA and/or IgM | Recurrent infections, may have IgA nephropathy |
| CD81 deficiency | CD81 | AR | Low IgG, low or normal IgA and IgM | Recurrent infections, glomerulonephritis, Henoch-Schönlein purpura |
| CD20 deficiency | CD20 | AR | Low IgG, normal or elevated IgM and IgA | Recurrent infections |
| CD21 deficiency | CR2 | AR | Low IgG, impaired antipneumococcal response | Recurrent infections |
| CD27 | CD27 | AR | Hypogammaglobulinemia | Recurrent infections; persistent EBV viremia |
| PIK3CD mutation (GOF) | PIK3CD GOF | AD | All isotypes decreased | Severe bacterial infections; decreased or absent pro-B cells, herpesvirus and EBV disease |
| NFKB1 deficiency | NFKB1 | AD | Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells | About 70% penetrant, recurrent sinopulmonary infections, EBV proliferation, autoimmune cytopenias, enteropathy, interstitial lung disease, aphthous lesions |
| NFKB2 deficiency | NFKB2 | AD | Low serum IgG, IgA, and IgM; low B-cell numbers | Recurrent sinopulmonary infections, alopecia, and autoimmune endocrinopathies |
| IKAROS deficiency | IKZF1 | AD | Low IgG and IgA and/or IgM; reduced B-cell numbers | Recurrent infections, ALL, some with autoimmunity |
| IL21 deficiency | IL21 | AR | Impaired B-cell differentiation | Inflammatory bowel disease, infections |
| IL21R deficiency | IL21R | AR | Low IgG, defective class-switched B cells, and defective antibody responses | Recurrent infections, cryptosporidial liver disease |
| LRBA deficiency | LRBA | AR | Hypogammaglobulinemia, low IgG and IgA defective class-switched B cells, expanded CD21low B cells | Chronic interstitial lung disease; autoimmunity; inflammatory bowel disease; endocrinopathy; infections |
| CTLA4 deficiency | CTLA4 | AD | Hypogammaglobulinemia, low IgG and IgA; sometimes IgM, defective class-switched B cells, expanded CD21low B cells | Not fully penetrant, mainly autoimmunity and inflammatory organ disease, infections, Hodgkin lymphoma |
| PIK3CD deficiency | PIK3CD | AD, AR | Hypogammaglobulinemia, increased IgM, defective class-switched B cells, expanded CD21low B cells, expanded CD57+ CD8 T cells | Recurrent infections, lymphoproliferation; autoimmunity, B-cell lymphoma |
| PIK3R1 deficiency | PIK3R1 | AD; AR | Hypogammaglobulinemia, increased IgM, defective class-switched B cells, expanded CD21low B cells | Recurrent infections, lymphoproliferation; B-cell lymphoma; neurodevelopmental delay |
| IRF2BP2 deficiency | IRF2BP2 | AD | Hypogammaglobulinemia | Recurrent infections, colitis |
Adapted from Picard et al.48
AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; EBV, Epstein-Barr virus; GOF, gain of function; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M.