Table 3.
Predominantly antibody deficiencies
| Disease | Genetic defect | Inheritance | OMIM | Ig | Associated features |
|---|---|---|---|---|---|
| 1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia | |||||
| BTK deficiency, X-linked agammaglobulinemia (XLA) | BTK | XL | 300300 | All isotypes decreased in majority of patients, some patients have detectable immunoglobulins | Severe bacterial infections, normal numbers of pro-B cells |
| μ heavy chain deficiency | IGHM | AR | 147020 | All isotypes decreased | Severe bacterial infections, normal numbers of pro-B cells |
| λ5 deficiency | IGLL1 | AR | 146770 | ||
| Igα deficiency | CD79A | AR | 112205 | ||
| Igβ deficiency | CD79B | AR | 147245 | ||
| BLNK deficiency | BLNK | AR | 604515 | ||
| p110δ deficiency | PIK3CD | AR | 602839 | Severe bacterial infections; autoimmune complications (IBD) | |
| p85 deficiency | PIK3R1 | AR | 615214 | Severe bacterial infections, cytopenias, decreased or absent pro-B cells | |
| E47 transcription factor deficiency | TCF3 | AD | 616941 | Recurrent bacterial infections | |
| TCF3 | AR | 147141 | Severe, recurrent bacterial infections, failure to thrive | ||
| SLC39A7 (ZIP7) deficiency | SLC39A7 | AR | 601416 | Early onset infections, blistering dermatosis, failure to thrive, thrombocytopenia | |
| Hoffman syndrome/TOP2B deficiency | TOP2B | AD | 126431 | Recurrent infections, facial dysmorphism, limb anomalies | |
| 2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID phenotype | |||||
| Common variable immune deficiency with no gene defect specified (CVID) | Unknown | Variable | Low IgG and IgA and/or IgM | Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease | |
| Activated p110δ syndrome (APDS) | PIK3CD GOF | AD | 615513 (APDS1) | Normal/increased IgM, reduced IgG and IgA | Severe bacterial infections; reduced memory B cells and increased transitional B cells, EBV ± CMV viremia, lymphadenopathy/splenomegaly, autoimmunity, lymphoproliferation, lymphoma |
| PIK3R1 | AD | 616005 (APDS2) | Severe bacterial infections, reduced memory B cells and increased transitional B cells, lymphadenopathy/splenomegaly, lymphoproliferation, lymphoma; developmental delay | ||
| PTEN deficiency (LOF) | PTEN | AD | 158350 | Normal/Decreased | Recurrent infections, Lymphoproliferation, Autoimmunity; developmental delay |
| CD19 deficiency | CD19 | AR | 107265 | Low IgG and IgA and/or IgM | Recurrent infections, may have glomerulonephritis (CD81 mutation abolishes expression of CD19, thereby phenocopying CD19 mutations) |
| CD81 deficiency | CD81 | AR | 186845 | Low IgG, low or normal IgA and IgM | |
| CD20 deficiency | CD20 | AR | 112210 | Low IgG, normal or elevated IgM and IgA | Recurrent infections |
| CD21 deficiency | CD21 | AR | 120650 | Low IgG, impaired anti-pneumococcal response | Recurrent infections |
| TACI deficiency# | TNFRSF13B | AR or AD | 604907 | Low IgG and IgA and/or IgM | Variable clinical expression and penetrance for monoallelic variants |
| BAFF receptor deficiency | TNFRSF13C | AR | 606269 | Low IgG and IgM, | Variable clinical expression |
| TWEAK deficiency | TNFSF12 | AD | 602695 | Low IgM and A, lack of anti-pneumococcal antibody | Pneumonia, bacterial infections, warts, thrombocytopenia. Neutropenia |
| TRNT1 deficiency | TRNT1 | AR | 612907 | B cell deficiency and hypogammaglobulinemia | congenital sideroblastic anemia, deafness, developmental delay |
| NFKB1 deficiency | NFKB1 | AD | 164011 | Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells | Recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia and autoimmune thyroiditis |
| NFKB2 deficiency | NFKB2 | AD | 615577 | Low serum IgG, A and M; low B cell numbers | Recurrent sinopulmonary infections, alopecia and endocrinopathies |
| IKAROS deficiency | IKZF1 | AD (haploinsufficiency) | 603023 | Low IgG, IgA, IgM, low or normal B cells; B cells and Ig levels reduce with age | Decreased pro-B cells, recurrent sinopulmonary infections; increased risk of ALL, autoimmunity, CVID phenotype |
| IRF2BP2 deficiency | IRF2BP2 | AD | 615332 | Hypogammaglobulinemia, absent IgA | Recurrent infections, possible autoimmunity and inflammatory disease |
| ATP6AP1 deficiency | ATP6AP1 | XL | 300972 | Variable immunoglobulin findings | Hepatopathy, leukopenia, low copper |
| ARHGEF1 deficiency | ARHGEF1 | AR | 618459 | Hypogammaglobulinemia; lack of antibody | Recurrent infections, bronchiectasis |
| SH3KBP1 (CIN85) deficiency | SH3KBP1 | XL | 300310 | IgM, IgG deficiency; loss of antibody | Severe bacterial infections |
| SEC61A1 deficiency | SEC61A1 | AD | 609213 | Hypogammaglobulinemia | Severe recurrent respiratory tract infections |
| RAC2 deficiency | RAC2 | AR | 602049 | Low IgG, IgA, IgM, low or normal B cells; reduced Ab responses following vaccination | Recurrent sinopulmonary infections, selective IgA deficiency; poststreptococcal glomerulonephritis; urticaria |
| Mannosyl-oligosaccharide glucosidase deficiency | MOGS | AR | 601336 | Low IgG, IgA, IgM, increased B cells; poor Ab responses following vaccination | Bacterial and viral infections; severe neurologic disease; also known as congenital disorder of glycosylation type IIb (CDG-IIb) |
| 3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper IgM | |||||
| AID deficiency | AICDA | AR | 6055258 | IgG and IgA decreased, IgM increased; normal memory B cells but lacking somatic hypermutation | Bacterial infections, enlarged lymph nodes and germinal centers; autoimmunity |
| AD | 605257 | IgG absent or decreased, IgA undetected, IgM increased; normal memory B cells with intact somatic hypermutation | Bacterial infections, enlarged lymph nodes and germinal centers. Mutations uniquely localize to the nuclear export signal. | ||
| UNG deficiency | UNG | AR | 191525 | IgG and IgA decreased, IgM increased | Enlarged lymph nodes and germinal centers |
| INO80 deficiency | INO80 | AR | 610169 | IgG and IgA decreased, IgM increased | Severe bacterial infections |
| MSH6 deficiency | MSH6 | AR | 600678 | Variable IgG, defects, increased IgM in some, normal B cells, low switched memory B cells, Ig class switch recombination and somatic hypermutation defects | Family or personal history of cancer |
| 4. Isotype, light chain, or functional deficiencies with generally normal numbers of B cells | |||||
| Ig heavy chain mutations and deletions | Mutation or chromosomal deletion at 14q32 | AR | One or more IgG and/or IgA subclasses as well as IgE may be absent | May be asymptomatic | |
| Kappa chain deficiency | IGKC | AR | 147200 | All immunoglobulins have lambda light chain | Asymptomatic |
| Isolated IgG subclass deficiency | Unknown | ? | Reduction in one or more IgG subclass | Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections | |
| IgG subclass deficiency with IgA deficiency | Unknown | ? | Reduced IgA with decrease in one or more IgG subclass | Recurrent bacterial infections | |
| May be asymptomatic | |||||
| Selective IgA deficiency | Unknown | ? | Absent IgA with other isotypes normal, normal subclasses and specific antibodies | May be asymptomatic Bacterial infections, autoimmunity mildly increased | |
| Specific antibody deficiency with normal Ig levels and normal B cells | Unknown | ? | Normal | Reduced ability to produce antibodies to specific antigens | |
| Transient hypogammaglobulinemia of infancy | Unknown | ? | IgG and IgA decreased | Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections | |
| CARD11 GOF | CARD11 | AD GOF | 616452 | Polyclonal B cell lymphocytosis due to constitutive NF-κB activation | Splenomegaly, lymphadenopathy, poor vaccine response |
| Selective IgM deficiency | Unknown | ? | Absent serum IgM | Pneumococcal/bacterial | |
Common variable immunodeficiency disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Identification of causal variants can assist in defining treatment. In addition to monogenic causes on this table, a small minority of patients with XLP (Table 4), WHIM syndrome (Table 6), ICF (Table 2), VODI (Table 2), thymoma with immunodeficiency (Good syndrome), or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia, and normal or reduced numbers of B cells
Total number of disorders in Table 3: 46
Total number of mutant genes in Table 3: 39
New disorders: 9: AR PIK3CD [46–48]; AR TCF3 [49, 50]; SLC39A7 [51]; TOP2B [52]; ARHGEF1 [53]; SH3KBP1 [54]; SEC61A1 [55]; AR LOF RAC2 [56]; AD AICDA
EBV Epstein-Barr virus, COPD chronic obstructive pulmonary disease
#Heterozygous variants in TNFRSF13B have been detected in healthy individuals, thus such variants are likely to be disease-modifying rather than disease-causing