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

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.