A novel protein truncating mutation of TTC8 causes Bardet-Biedl Syndrome (BBS) in a Pakistani family.

This study looked at a Pakistani family where multiple members had Bardet-Biedl Syndrome (BBS) to find the genetic cause of their condition. The researchers used advanced genetic testing called whole-exome sequencing to examine all the genes in the family's DNA. The scientists discovered a new genetic mutation (change) in a gene called TTC8 that hadn't been seen before in BBS patients. This mutation causes the gene to produce a shortened, broken protein that can't work properly. When they used computer models to study this broken protein, they found it would likely disrupt an important cellular structure called the "BBSome complex," which helps cells function normally. The damage to this complex is what leads to the symptoms of BBS. This discovery is important because it expands our understanding of the different genetic causes of BBS and adds to the list of mutations that can cause the condition. While this research doesn't offer new treatments, it helps doctors better understand the condition and could improve genetic testing and counseling for families. It may also help doctors provide more accurate diagnoses and genetic counseling for other families who might be at risk for having children with BBS.

Bardet-Biedl syndrome (BBS) is a rare ciliopathic disorder that segregates in an autosomal recessive manner. Genetic studies have so far identified 26 BBS-associated genes worldwide. This study analyzed a multiplex consanguineous Pakistani family with Bardet-Biedl syndrome. Genetic analysis was performed using whole-exome sequencing and Sanger sequencing. Additionally, in silico predictions were performed for functional characterization of the identified mutation. Whole exome analysis of this family identified a novel nonsense mutation [(NM_144596: exon11:c.C1047G: p.(Tyr349*)] in the 11th exon of TTC8 gene. The identified mutation presumably leads to removal of four TPR domains and C-terminus portion. Structural analyses of mutant TTC8 protein showed substantial morphologic and interactional variations, suggesting a defective role of the TTC8 protein in BBSome complex and thus its involvement in disease progression. Identification of novel mutation has expanded the mutational spectrum of TTC8. Moreover, these findings will help in genotype-phenotype association, prenatal diagnosis and genetic counseling of families at risk of BBS syndrome.