Computational and Structural Analysis to Assess the Pathogenicity of Bardet-Biedl Syndrome Related Missense Variants Identified in Bardet-Biedl Syndrome 10 Gene (BBS10)

ACS Omega. 2022 Oct 12;7(42):37654-37662. doi: 10.1021/acsomega.2c04522. eCollection 2022 Oct 25.


Bardet-Biedl Syndrome (BBS) is a rare inherited disorder resulting in multiple organ dysfunctions, whose cardinal clinical features include cognitive impairment, obesity, and renal dysfunction. Although it is highly heterogeneous at genetic levels, BBS10 is one of the major causative genes worldwide. The BBS10 protein is part of a multiprotein complex localized at the basal body of the primary cilium. With the advancement of sequencing technologies, novel missense mutations are regularly reported in BBS10. However, prioritizing missense variants and conducting further in-depth analysis are key challenges in addressing their pathogenic effect. This study aims to characterize the known missense mutations of BBS10 by combining nine different in silico tools (SIFT, SNAP2, PROVEAN, Align-GVGD, ConSurf, I Mutant, MuPro, PremPS, and Dynamut) and molecular dynamics (MD) simulations. A total of 101 BBS10 missense variants have been analyzed. Our results showed that six BBS10 missense variants (Ser191Leu, Cys19Gly, Ile342Thr, Cys371Ser, Ala417Glu, and Tyr613Cys) were potentially deleterious. Overall, this study provides a comprehensive workflow for screening BBS10 missense mutations to identify pathogenic variants effectively.