Investigation of genetic variants causing Bardet–Biedl syndrome in Iranian families: Identification of a founder mutation in BBS2, p.T157T

Abstract

Abstract Background Bardet-Biedl Syndrome (BBS) is a rare inherited ciliopathy disorder characterized by a wide range of clinical symptoms affecting multiple body systems. All BBS genes are involved in cilia function as a part of the BBSome complex. Mutations of BBS genes are not completely understood, suggesting that more research is needed to develop a molecular diagnostic strategy for this syndrome. Methods and Results Whole exome sequencing (WES) was performed on eighteen patients. A comparative study based on Runs of homozygosity (ROH (calling was performed using the BCFtools/RoH software on WES data. The potential pathogenicity of the detected mutations and the effect on splicing was predicted by in-silico analysis. Copy Number Variation (CNV) analysis was performed from the read depth of WES data using the ExomeDepth pipeline in unsolved BBS patients. Eight variants including four novel mutations, and a synonymous splicing variant (c.G471A) in BBS2 were identified. By examining homozygous regions among these patients, the existence of common homozygous regions containing the identified mutation was proved in patients with Baloch ethnicity. In-silico analysis predicted the effect of the c.G471A mutations on BBS2 mRNA splicing, this mutation leads to broken wild-type donor site and intron retention in the mature mRNA. CNV analysis revealed a deletion of exons in the BBS1 gene. Conclusion Our results declared the founder mutation c.G471A in the BBS2 gene in the Baloch ethnicity of the Iranian population, which can determine the diagnostic approach of this syndrome in future studies.