Submission Details

TNFRSF13B was first reported in relation to autosomal recessive common variable immunodeficiency 2 (CVID 2) in 2001 (Salzer U, et al., 2005, PMID: 16007087 and Castigli E, et al., 2005, PMID: 16007086). TNFRSF13B encodes TACI (transmembrane activator and CAML interactor), a transmembrane protein of the TNF receptor superfamily found predominantly on the surface of B cells. TACI is a receptor on B cells for APRIL, BAFF, syndecan-2, besides interacting with CAML. TACI mediates activation of transcription factors NF-AT, NF-kappa-B, and AP-1, and is involved in the stimulation of B- and T-cell function and the regulation of humoral immunity. CVID is a clinically and genetically heterogeneous entity, primarily presenting as an antibody deficiency with low levels of serum IgG, IgA, and/or IgM, functional antibody deficiency, and recurrent sinopulmonary bacterial infections. In addition, non-infectious complications linked to underlying immune dysregulation are present in a subset of patients. Evidence supporting the TNFRSF13B gene-disease relationship includes case-level data and experimental data. At least 14 unique variants have been reported in humans with biallelic variants, including nonsense, frameshift, splicing, and missense. Biallelic variants in this gene have been reported in at least 12 probands in 7 publications (PMIDs: 16007086, 19779048, 19629655, 27123465, 16007087, 18981294, 17983875), and segregated with disease in four additional family members. Experimentally, this gene-disease relationship is supported by its expression in B cells (PMID: 15240667), its role in class switch recombination (PMID: 15630136), which is altered in patient cells (PMID: 16007087), and two mouse models (PMIDs: 11429549, 11371359) which recapitulate features of CVID. In summary TNFRSF13B is definitively associated with autosomal recessive CVID 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, variants in TNFRSF13B have been observed in CVID patients in both the monoallelic and biallelic forms. Heterozygous mutations in TNFRSF13B may lead to impaired ligand binding and contribute to defects in cell activation and B cell tolerance, but the connection between heterozygous mutations and disease is not clear, because normal relatives may have the same mutations without evidence of immune deficiency. Since additional genetic or environmental factors are required to induce immune deficiency, only biallelic cases are considered here for the relationship between TNFRSF13B and CVID 2. On the other hand, heterozygous TACI variants do affect B cell activation and peripheral tolerance resulting in autoimmunity (Romberg et al., 2013; PMID: 24051380), likely due to a dominant negative effect (Romberg et al., 2015; PMID: 26100089). Whereas, patients with Smith-Magenis syndrome (with a deletion on 17p) have haploinsufficiency of TACI but do not develop autoimmunity or abnormal B cell function. Additionally, epistatic interactions have been reported between TNFRSF13B and other genes, such as TCF3 with similar function, resulting in a digenic cause of humoral immunodeficiency (Ameratunga et al., 217; PMID: 29114388).