Predominantly antibody deficiency (PAD) is the most prevalent form of human inborn errors of immunity (IEI). PAD is characterized by recurrent bacterial infections, immune dysregulation, and impaired immunoglobulin production. A monogenic cause of PAD can be identified in about 20% of cases. Approximately 10% of patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding the B cell surface protein TACI. Heterozygous variants in TNFRSF13B are not sufficient to cause PAD, as approximately 1% of the healthy population carries one of these variants. To identify additional genetic contributors to the immune defect in these individuals, we examined the exomes of 161 PAD patients with rare-damaging variants in TNFRSF13B. We identified (i) biallelic mutations in TNFRSF13B, (ii) the HLA-class II marker (DPA1*03), and (iii) multiple single nucleotide polymorphisms in known B-cell related genes, as additional genetic risk factors. Moreover, pathogenic mutations in other known IEI genes were presented in 16% of patients with heterozygous TNFRSF13B variants.
Keywords: Inborn errors of immunity; TACI; TNFRSF13B; antibody deficiency; common variable immunodeficiency; immunoglobulin A deficiency; modifier genes; phenotypic expression; primary immunodeficiency.