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Introduction
Bardet-Biedl syndrome (BBS; MIM 209900) is a canonical ciliopathy characterised by retinitis pigmentosa, obesity, kidney alteration, dystrophic extremities, behavioural dysfunction and hypogonadism. 1 Rapidly evolving strategies ranging from traditional homozygosity mapping to next generation sequencing (NGS) approaches have uncovered 17 BBS genes.
Primary cilia dysfunction underlies the pathogenesis of BBS; indeed, eight proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP1/BBIP10) have been shown to form the BBSome, 2 3 a stable complex involved in signalling receptor trafficking to and from cilia. BBS6, BBS10 and BBS12 assemble into a chaperonin complex that mediates BBSome assembly. BBS3/ARL6 recruits the BBSome to membranes, and BBS17/LZTFL1 regulates BBSome entry into cilia. BBSome cargos include Smoothened, a component of the Sonic Hedgehog (Shh) signalling pathway, 4 and Somatostatin Receptor 3, a G-protein-coupled receptor. 5
Mutations found in the 17 known BBS genes are found in 80% of BBS patients while 20% of them still lack molecular diagnosis. 6 Through exome sequencing, we report the first BBS patient carrying a mutation in the BBIP1 gene (also known as BBIP10 standing for the BBSome Interacting Protein 1/of 10 kDa) encoding the eighth subunit of the BBSome. 2 Given our prior characterisation of BBIP1 as a BBSome subunit essential for BBSome assembly 2 and given the severely reduced levels of BBIP1 in the patient's fibroblasts, we propose BBIP1 as the 18th BBS gene.
Methods
Family selection
Among 450 BBS families screened, about 15% were devoid of mutation in known BBS genes. We report herein one of our BBS families analysed by exome sequencing.
Informed consent and ethical approval of the patient and his/her representative were obtained according to the French legislation. The objectives and the aim of the study were clearly explained to the patient.
Whole exome sequencing and SNP calling
Whole exome sequencing was performed by IntegraGen. Exons of DNA samples were captured using the in-solution SureSelect Target Enrichment System (Agilent, Human All Exon Kits v2), followed by a paired-end high-throughput sequencing on reads of 75 bp using the Illumina HiSeq 2000. Image analysis and base calling were performed with default parameters of Illumina RTA v1.14 pipeline. The alignment of clean reads on the human reference genome (hg19/GRCh37) and single nucleotide polymorphism (SNP) calling were performed with CASAVA...