Integrative Analysis of the TNFRSF13B Variants in Common Variable Immune Deficiency

Abstract Background: TNF receptor superfamily member 13B ( TNFSRF13B ) is a member of the TNF superfamily which is crucial for B cell maturation, plasma cell differentiation and antibody response. Impaired expression of TNFRSF13B gene was associated with common variable immune deficiency (CVID), selective IgA deficiency, autoimmunity and/or lymphoproliferation disorders. Beside disease-causing variants of this gene, the polymorphisms can be associated with strong or weak TNFRSF13B expression that leads to unbalanced B cell response and increased autoreactive antibody production. Materials and Methods: Within the scope of this paper, we detect 26 variants (three synonymous, five missense, eleven UTR, seven intronic variants) in the TNFRSF13B gene by screening 80 pediatric and adult CVID patients. Results: Beyond categorization of these detected variants as likely benign, benign, or variant of uncertain significance, we perform an integrative bioinformatics approach to provide a plausible explanation for CVID associations of these detected variants from different perspectives, e.g. missense variants from a thermodynamical point of view, UTR variants from regulatory issues, synonymous variants in RNA binding perspectives and so on. 58% of (15/26) detected variants were altered regulatory elements, such as transcription factor binding or miRNA binding sites and splice site regions or thermodynamic impact on protein. Thirteen variants were found to have at least tenfold increased allele frequencies compared to global databases indicating TNFRSF13B variants which have a potential regulatory effect, more common in CVID patients. Conclusions: All findings have suggested that the presence of these variants may not be the causative variant for CVID phenotype but might be associated with minimal or moderate regulatory impacts on CVID patients. This study also emphasizes the importance of using the integrative bioinformatic approach to identify promising variants.