Mutation profile of BBS genes in patients with Bardet\u2013Biedl syndrome: an Italian study

Elena Manara,Stefano Paolacci,Luca Rossetti,Luca Buzzonetti,Leonardo Colombo,Benedetto Falsini,Giulia Guerri,Balzarini Marta,Loredana Boccone,Fabiana D’Esposito,Lucia Ziccardi,Giancarlo Iarossi,Alba Pilotta,Marica Monica,Andi Abeshi,Paolo Enrico Maltese,Matteo Bertelli

doi:10.1186/s13052-019-0659-1

Abstract

BackgroundBardet–Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance. There is currently no treatment for BBS, but some morbidities can be managed. Accurate molecular diagnosis is often crucial for the definition of appropriate patient management and for the development of a potential personalized therapy.MethodsWe developed a next-generation-sequencing (NGS) protocol for the screening of the 18 most frequently mutated genes to define the genotype and clarify the mutation spectrum of a cohort of 20 BBS Italian patients.ResultsWe defined the causative variants in 60% of patients; four of those are novel. 33% of patients also harboured variants in additional gene/s, suggesting possible oligogenic inheritance. To explore the function of different genes, we looked for correlations between genotype and phenotype in our cohort. Hypogonadism was more frequently detected in patients with variants in BBSome proteins, while renal abnormalities in patients with variations in BBSome chaperonin genes.ConclusionsNGS is a powerful tool that can help understanding BBS patients’ phenotype through the identification of mutations that could explain differences in phenotype severity and could provide insights for the development of targeted therapy. Furthermore, our results support the existence of additional BBS loci yet to be identified.

Highlights

Bardet–Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance
The genes mostly code for proteins forming the core BBSome complex (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9) or part of a Bardet-Biedl syndrome (BBS) chaperone complex (BBS6, BBS10 and BBS12) which plays an essential role in the stabilization and regulation of the BBSome [3, 4]
The 20 patients with Bardet-Biedl syndrome enrolled in this study were screened using a panel of 18 genes associated with the disease

Summary

Introduction

Bardet–Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance. Bardet-Biedl syndrome (BBS) is a rare inherited, clinically and genetically heterogeneous, multisystemic ciliopathy with various primary and secondary clinical manifestations [1]. Twenty-one different loci (BBS1-BBS21) have been associated with this syndrome. Other genes code for proteins with roles in the localization and activation of BBSome (ARL6) or BBSome entry into cilia (BBS17) or are associated with the BBSome complex (BBS14) (Fig. 1 and Additional file 1: Table S1). BBSome is a stable protein complex that functions in the biogenesis and maintenance of the primary cilium (Fig. 1), a structure that is ubiquitously expressed and highly

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Conclusion