Whole Genome Sequencing solves an atypical form of Bardet-Biedl Syndrome, where Whole Exome Sequencing fails: identification of novel biallelic variants of BBS9

ID: 11078 In recent years, it is becoming increasingly evident that whole-exome sequencing (WES) is not always the most fruitful approach to reach the molecular basis of rare diseases. Here, we present the case of 18 years-old boy complaining severe photophobia and central visual loss since childhood, and referring hexodactyly of the right foot and supernumerary nipple at birth, suggestive of Bardet-Biedl syndrome. Family history was negative for consanguinity and for degenerative visual abnormalities in his parents and siblings. Genetic analyses, performed using targeted resequencing and WES, were not able to identify any exhaustive genetic defect. Therefore, we decided to carry out whole-genome sequencing (WGS), which allowed us to identify two biallelic pathogenic variants in the BBS9 gene, namely a missense variant (c.545G>C; p.Gly182Ala) and a previously undetected rare intronic deletion of ~1.2Kb encompassing exon thirteen (chr7_33348318_33349583_del). Bardet-Biedl syndrome (BBS) is a rare hereditary multisystem disorder first described in 1920, characterized by retinitis pigmentosa, obesity, postaxial polydactyly, cognitive deficits, and genitourinary defects. The syndrome-associated genes named BBS1 to BBS21 have been established to codify for proteins of an octameric complex called the BBSome, which plays a central role in primary cilium generation and function. Among the BBS genes, the disease-causing gene BBS9 (aka PTHB1) encodes for BBS9 protein, which is the core element of the BBSome, interacts with almost all other subunits and is therefore considered behave as aggregator into the core of the complex. Indeed, together with BBS2 and BBS7, it forms the ternary intermediate from which the entire BBSome assembles and reaches the cilium. In this study, we assessed the functional impact of the identified BBS9 variants on patient-derived fibroblasts, and demonstrated that they impair stability of the BBS9 protein, with significant consequences in genesis and size of primary cilium. Overall, this study highlights the importance of WGS in clarifying clinical diagnosis and its challenge to reliably identifying rare intragenic structural variants in the genetic workup of rare diseases. In this context, the functional validation of these rare variants is necessary to assess their pathogenicity.