Whole Exome Sequencing in 11 Iranian Patients Expands the Mutational and Clinical Spectrum of Bardet- Biedl Syndrome

Abstract Objective: Bardet-Biedl syndrome (BBS, OMIM 209900) is a rare autosomal recessive disorder characterized by a broad spectrum of clinical features including renal anomalies, learning disabilities, postaxial polydactyly, retinal dystrophy, obesity, and hypogenitalism. BBS is a heterogeneous syndrome, both genetically and clinically. To date, genetic variants in more than 28 genes have been associated with this syndrome and its subtypes. Most previous studies on BBS have failed to show clear genotype–phenotype correlations. Design and Methods: In order to investigate the spectrum of genetic variation among Iranian BBS patients, 11 subjects from 9 families with clinically diagnosed BBS were included in this study. Following informed consent, we applied whole exome sequencing (WES) to the proband and their parents. We next performed Sanger sequencing to validate the identified variants. Results: WES successfully identified three variants in the BBS9 gene: c.2014C>T, c.1789+1 G>A, and a novel deletion of exon 16. Two novel variants were identified in the BBS7gene: c.880G>C and c.719G>A. In addition, one novel variant was found in each of the CEP290 gene (c.5159C>G), TTC8 gene (c.462_465del), and MKKS gene (c.515_516delCT). One previously reported variant was also detected in the BBS10 gene (c.728_731del). Among the clinical manifestations observed, obesity and polydactyly were the most common findings. Conclusions: Our findings further support the high heterogeneity of BBS: by discovering six novel variants, we expand the mutational spectrum of BBS-related genes and contribute to the understanding of this multisystem disease.