Characterizing Homozygous Variants in Bardet-Biedl Syndrome-Associated Genes Within Iranian Families: Unveiling a Founder Variant in BBS2, c.471G>A.

Abstract

Bardet-Biedl syndrome (BBS) is a rare inherited ciliopathy disorder characterized by a broad spectrum of clinical symptoms such as retinal dystrophy, obesity, polydactyly, genitourinary and kidney anomalies, learning disability, and hypogonadism. The understanding of the variants involved in BBS-causing genes remains incomplete, highlighting the need for further research to develop a molecular diagnostic strategy for this syndrome. Singleton whole-exome sequencing (WES) was performed on sixteen patients. Our study revealed (1) nine patients carried eight homozygous pathogenic variants with four of them being novel (2) Specifically, a synonymous splicing variant (c.471G > A) in BBS2 gene in six patients with Baloch ethnicity. The identification of runs of homozygosity (ROH) calling was performed using the BCFtools/RoH software on WES data of patients harboring c.471G > A variant. The presence of shared homozygous regions containing the identified variant was confirmed in these patients. In-silico analysis predicted the effect of the c.471G > A variants on BBS2 mRNA splicing. This variant results in disrupted wild-type donor site and intron retention in the mature mRNA. (3) And a deletion of exons 14 to 17 in the BBS1 gene was identified in one patient by Copy-Number Variation (CNV) analysis using the ExomeDepth pipeline. Our results identified the founder variant c.471G > A in the BBS2 gene in the Baloch ethnicity of the Iranian population. This finding can guide the diagnostic approach of this syndrome in future studies.