Alternative titles; symbols
ORPHA: 696907; DO: 0081145; MONDO: 0009413;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p11.2 | Immunodeficiency, common variable, 2 | 240500 | Autosomal dominant; Autosomal recessive | 3 | TNFRSF13B | 604907 |
A number sign (#) is used with this entry because this form of common variable immunodeficiency (CVID), referred to here as CVID2, is caused by heterozygous, homozygous, or compound heterozygous mutation in the TNFRSF13B gene (604907), which encodes the transmembrane activator and CAML interactor (TACI), on chromosome 17p11.
Selective IgA deficiency-2 (IGAD2; 609529) can also be caused by mutation in the TNFRSF13B gene.
For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Salzer et al. (2005) reported 2 unrelated families with a diagnosis of common variable immunodeficiency. All affected individuals had hypogammaglobulinemia with low serum IgG, IgM, and IgA, and recurrent infections, including otitis media, respiratory tract infections, and gastrointestinal tract infections. In a third family, 1 individual had recurrent infections, splenomegaly, and decreased IgG, and died of tonsillar carcinoma of epithelial origin. His sister had selective IgA deficiency-2 (IGAD2; 609529) with recurrent infections. Ten patients with sporadic disease were also identified. Four (31%) of 13 probands had autoimmune phenomenon, including thyroiditis, and 6 of 13 had splenomegaly. Laboratory studies in all patients showed normal total numbers of peripheral B cells, except in 1 patient who had undergone splenectomy and his brother who had slightly increased B-cell numbers, but a decrease of switched memory B cells. The T-cell compartment was normal in all patients.
Castigli et al. (2005) reported 4 unrelated individuals with antibody deficiency due to mutation in the TNFRSF13B gene. All presented with recurrent sinopulmonary infections requiring intravenous Ig therapy. Serum IgG and IgA were low, and serum antibody response to immunization with pneumococcal vaccine was decreased, although T cell-dependent response to tetanus toxin was normal. One proband developed a B-cell non-Hodkgin lymphoma, and her mother, who had recurrent infections, died of lymphoma. An affected sister died of gastrointestinal carcinoma. In contrast to Salzer et al. (2005) who found decreased IgM in their patients, Castigli et al. (2005) reported normal levels of serum IgM in their patients.
In patients with CVID2, Salzer et al. (2005) and Castigli et al. (2005) confirmed both autosomal dominant and autosomal recessive inheritance.
By studying cohorts of immunodeficient individuals from Europe (162 individuals with a diagnosis of CVID) and the US (19 individuals with CVID and 16 with IGAD), Salzer et al. (2005) and Castigli et al. (2005) found that mutations in the TNFRSF13B gene were associated with familial and sporadic forms of the disease (see, e.g., 604907.0001-604907.0005). Individuals had homozygous, heterozygous, or compound heterozygous mutations, and some families segregated both CVID2 and IGAD2. Martin and Dixit (2005) noted that 3 of the 6 mutations were found in both cohorts and were seen in both familial and sporadic cases, suggesting that a small number of common mutations could account for most TACI-associated immunodeficiency cases.
Salzer et al. (2009) identified at least 1 altered TNFRSF13B allele in 50 (8.9%) of 564 probands with antibody deficiency. Of those 50 unrelated patients, 2 (4%) carried homozygous mutations, 7 (14%) carried compound heterozygous mutations, and 41 (82%) carried heterozygous mutations. Sixteen different genetic alterations were identified, including 13 novel changes. The most common alleles were C104R (604907.0001) and A181E (604907.0002), found in 26 (4.6%) and 13 (2.3%) patients, respectively. Only these 2 alleles were observed in a homozygous state, each in 1 individual. Among 675 controls, 7 (1%) were heterozygous for A181E, and 6 (0.9%) were heterozygous for C104R. Statistical analysis showed that a mono- or biallelic TNFRSF13B allele conferred a relative risk of 3.6 for developing hypogammaglobulinemia. The association was particularly strong for C104R (relative risk of 4.2), but not for A181E. Analysis of 7 families indicated reduced penetrance of the alleles and suggested that TNFRSF13B variations are a contributing factor to the development of CVID, but are not solely causative. Patients with TNFRSF13B mutations were more likely to have manifestations of autoimmunity, usually thrombocytopenia, or lymphoproliferation compared to those without mutations.
Castigli, E., Wilson, S. A., Garibyan, L., Rachid, R., Bonilla, F., Schneider, L., Geha, R. S. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature Genet. 37: 829-834, 2005. [PubMed: 16007086] [Full Text: https://doi.org/10.1038/ng1601]
Martin, F., Dixit, V. M. Unraveling TACIt functions. Nature Genet. 37: 793-795, 2005. [PubMed: 16049503] [Full Text: https://doi.org/10.1038/ng0805-793]
Salzer, U., Bacchelli, C., Buckridge, S., Pan-Hammarstrom, Q., Jennings, S., Lougaris, V., Bergbreiter, A., Hagena, T., Birmelin, J., Plebani, A., Webster, A. D. B., Peter, H.-H., and 21 others. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113: 1967-1976, 2009. [PubMed: 18981294] [Full Text: https://doi.org/10.1182/blood-2008-02-141937]
Salzer, U., Chapel, H. M., Webster, A. D. B., Pan-Hammarstrom, Q., Schmitt-Graeff, A., Schlesier, M., Peter, H. H., Rockstroh, J. K., Schneider, P., Schaffer, A. A., Hammarstrom, L., Grimbacher, B. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nature Genet. 37: 820-828, 2005. [PubMed: 16007087] [Full Text: https://doi.org/10.1038/ng1600]