Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes

Bardet-Biedl Syndrome (BBS) is a rare, autosomal-recessive ciliopathy characterized by obesity, rod-cone dystrophy, postaxial polydactyly, renal abnormalities, genital abnormalities and learning difficulties. To date, mutations in 21 different genes have been described as being responsible for BBS. Recently sequential gene sequencing has been replaced by next generation sequencing (NGS) applications. In this study, 15 patients with clinically diagnosed BBS were investigated using a next generation sequencing panel which included 17 known BBS causing genes (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, NPHP6, WDPCP, SDCCAG8, NPHP1).A genetic diagnosis was achieved in 13 patients (86.6%) and involved 9 novel and 3 previously described pathogenic variants in 6 of 17 BBS causing genes. BBS10 and BBS1 were the most commonly involved genes with frequencies of 31% and 23% respectively. Three of the 13 patients had an affected sibling. All affected siblings were found to be homozygous for the mutation detected in the proband. No evidence of triallelic inheritance was detected.Although limited association between certain genes and phenotypic features has been observed in this study, it is considered that additional studies are needed to better characterize the genotype–phenotype correlation of BBS. Our results demonstrate that NGS panels are feasible and effective method for providing high diagnostic yields in the diseases caused by multiple genes such as BBS.