Exome Sequencing in 9 Iranian Patients Expands the Mutational and Clinical Spectrum of Bardet-Biedl Syndrome.

This study looked at the genetic causes of Bardet-Biedl Syndrome (BBS) in 9 Iranian families by using advanced genetic testing called "exome sequencing" - a method that reads most of the DNA code to find changes that might cause disease. The researchers tested children with BBS and their parents to understand what genetic changes were responsible for the condition. The study found several different types of genetic changes in various BBS-related genes. Some of these changes had been seen before in other patients, but the researchers also discovered several completely new genetic changes that hadn't been reported before. They found changes in genes called BBS7, BBS9, BBS10, CEP290, MKKS, and TTC8. Among the patients studied, obesity and extra fingers/toes (polydactyly) were the most common symptoms. This research is important because it helps expand our understanding of how many different genetic changes can cause BBS and shows that the condition can be caused by problems in many different genes. While this study doesn't directly lead to new treatments, having a better "genetic map" of BBS could eventually help doctors provide more personalized care and might help researchers develop targeted therapies in the future. The findings also help families get more accurate genetic counseling about the condition.

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 hypogonadism. 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. In order to investigate the spectrum of genetic variation among Iranian BBS patients, 9 subjects from 9 different families with clinically diagnosed BBS were included in this study. Following informed consent, we applied exome sequencing (ES) to the proband and their parents. We next performed Sanger sequencing to validate the identified variants. ES successfully detected four known variants: two in the BBS9 gene, c.2014C > T (p.Gln672Ter) and c.1789 + 1 G > A, one variant in the BBS10 gene (c.728_731del; p.Lys243Ilefs*15), and one variant in the MKKS gene (c.515_516del; p.Glu172Alafs*19). ES also detected two new variants in the BBS7 gene, c.880G > C (p.Gly294Arg) and c.719G > A (p.Gly240Asp), one new variant in the CEP290 gene, c.5159C > G (p.Thr1720Arg), and one new variant, in the TTC8 gene, c.462_465del (p.Ser155Glufs*20). In addition, ES identified one novel homozygous deletion of exon 16 in the BBS9 gene. Among the clinical manifestations observed, obesity and polydactyly were the most common findings. Our findings further support the high heterogeneity of BBS: by discovering known, new, and novel pathogenic variants. We expand the mutational spectrum of BBS-related genes and contribute to the understanding of this multisystem disease.