Common Variable Immune Deficiency/IgA Deficiency via the TNFRSF13B Gene

Common Variable Immune Deficiency (CVID) is a disorder characterized by impaired humoral immunity resulting in infection susceptibility. Symptom onset is typically from age two to early adulthood with CVID affecting approximately one in 25,000 births, making it the most prevalent primary immunodeficiency. The most common genetic cause of CVID is mutation in the TNFRSF13B gene which accounts for 15-20% of cases (Salzer et al. 2005; Castigli et al. 2005). CVID may also be caused through mutations in the ICOS, BAFFR or CD19 genes and represent <1% of cases. Mutations in the TNFRSF13B gene also cause a phenotypically similar disorder, IgA Deficiency (IgAD). Genetic testing is helpful in differential diagnosis from other similar immunodeficiencies including agammaglobulinemia, ataxia-telangiectasia, severe combined immunodeficiency, WHIM syndrome, Wiskott-Aldrich syndrome, and X-linked lymphoproliferative disease (see related tests for detailed information on individual disorders). Treatment of CVID often includes immunoglobulin replacement therapy but may include splenectomy (Scharenberg et al. 2006; Wong et al. 2013). Patients with CVID through mutation in the TNFRSF13B gene are inherently susceptible to lymphoma. Therefore, genetic testing is helpful in determining if periodic CBC and WBC counts are required for surveillance of lymphoma (da Silva et al. 2011).

In 75% of CVID cases, the genetic underpinnings are unknown. The remaining cases of CVID are inherited in an autosomal dominant manner through mutations in the TNFRSF13B (15-20%) gene or an autosomal recessive mode through mutations in the ICOS, BAFFR, or CD19 genes (Scharenberg et al. 2006; Castigli and Geha 2006; Salzer et al. 2005). In rare cases, CVID has been shown to be inherited in an autosomal recessive manner through TNFRSF13B gene mutations. Mutations are found throughout the TNFRSF13B gene in CVID patients with about 90% of cases being sporadic. Two missense mutations, c.310T>C (p.Cys104Arg) and c.542C>A (p.Ala181Glu) are most commonly found and represent about 80% of all CVID cases through TNFRSF13B mutations (Salzer et al. 2009). Nonsense, splicing alterations, small insertions and small deletions have also been reported in a few cases (Salzer et al. 2009). While severity of symptoms may vary, disease penetrance is complete (Scharenberg et al. 2006).

The TNFRSF13B gene encodes the B-cell tumor necrosis factor surface receptor, transmembrane activator, and CAML interactor. Signaling by the APRIL and BAFF ligands through this receptor in conjunction with cytokine stimulation of the B-cell is required for antibody class switching which important for strengthening immunity during infection (Castigli et al. 2005).

Three separate reports were able to identify causative mutations in the TNFRSF13B gene in 50 of 564 (9%) patients with hypogammaglobulinemia, 5 of 20 (25%) individuals with CVID, and 13 of 162 (8%) individuals with CVID (Salzer et al. 2009; Castigli et al. 2005; Salzer et al. 2005). In 75-80% of cases with CVID, the cause is unknown (Scharenberg et al. 2006). Analytical sensitivity should be very high as all causative variants reported to date for CVID and IgAD are detectable by this methodology.

This test provides full coverage of all coding exons of the TNFRSF13B gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).