ClinVar

In 2 sibs, born of consanguineous parents, with adult-onset common variable immunodeficiency-4 (613494), Warnatz et al. (2009) identified a homozygous 24-bp in-frame deletion (del89_96) in exon 2 of the TNFRSF13C gene, resulting in the removal of a stretch of 8 hydrophobic amino acids from the transmembrane region. The mutation was not found in 100 controls. The mutant protein was not identified in immortalized patient lymphocytes, indicating that it was likely unstable. The proband was a 57-year-old man with a lifelong history of chronic sinusitis and adult-onset recurrent pneumonia. His 80-year-old sister had an unremarkable medical history except for a severe Herpes zoster infection at age 70. Laboratory studies of both patients showed very low serum IgG and IgM, but normal mucosal IgA. Both individuals also had a severe and persistent B-cell lymphopenia and reduced numbers of class-switched memory B cells. Surface protein phenotyping of the B cells showed a developmental arrest after the transitional stage and before the cells became mature follicular B cells. In vitro functional expression studies showed that the mutant protein failed to bind BAFF (603969) and failed to induce downstream NFKB (164011) processing. Warnatz et al. (2009) emphasized the phenotypic differences in the patients, which suggested residual sufficient potential to develop B cells that can differentiate and provide host defense even in the absence of BAFFR function.