Evaluating BAFF-Receptor variant pPro21Arg’s role in common variable immunodeficiency 2386

Abstract Description Common variable immunodeficiency (CVID) is a common inborn error of immunity, but a monogenic cause is rare. Biallelic loss-of-function pathogenic variants in the gene encoding BAFF-Receptor (TNFRSF13C) is one such cause. A common missense variant in BAFF-R, p.Pro21Arg, was proposed as contributing to the pathogenesis of non-monogenic CVID by Peiper et al. 2014 with an allelic frequency of 6.7% in controls versus 10.2% in CVID patients (OR 1.57, p = 0.0026) and Block et al. 2023 with an 11.36% allele frequency in CVID when compared to the Non-Finnish European population in the gnomAD database (OR = 1.316, p = 0.0145) and to an internal cohort of controls (OR = 1.316, p = 0.0458). Exact population composition matching is critical, as the frequency of this variant is highly variable even in Europe. We found the allelic frequency of BAFF-R p.Arg21Pro to be 10% from 90 non-familial CVID patients from the University of Utah Health Sciences Center, similar to Pieper et al. (10.2%) and Block et al. (11.36%), but comparing our Utah CVID patients to the 1000 Genomes project Utah Residents (CEU) with Northern and Western European Ancestry, which matches our CVID cohort (9.6% allelic frequency); we obtained an OR of 1.0468 (95% CI: 0.5309 to 2.0638; p = 0.8950). For further studies on BAFF-R p.Pro21Arg, we recommend closely matching the reference populations, and not using a broad European or other control populations. Topic Categories Translational and Interventional Immunology (TI)