Identification of 28 novel mutations in the Bardet–Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease

Abstract

Bardet–Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Arrayed primer extension technology simplifies mutation detection in Bardet–Biedl and Alström syndrome

“…This finding could be explained by the existence of two 'common' mutations in BBS1 and BBS10, identified in 71.1% (59/83) of BBS families; these mutations have been proposed previously for first pass screening. 10 In addition, most laboratories testing ALMS families, offer direct ALMS1 sequencing of only exons 16, 10, and part of 8, which would identify the mutations most frequently found in ALMS1. However, other alternative approaches based on massive sequencing are not, at this time, as practical or cost-effective as the genotyping chip.…”

In search of triallelism in Bardet–Biedl syndrome

“…This detection rate is higher than what is described in other studies. 29,44 Indeed, 75% detection rate is commonly cited in the literature. Clearly, genetic homogeneity and founder effect in the study population cannot be invoked as plausible explanations to our high detection rate as they are in direct contradiction to what we observed in this study.…”

“…[19][20][21][22][23][24][25] Others, however, failed to demonstrate this oligogenic model and debate continues as to the magnitude of oligogenicity in the inheritance of BBS. 12,[26][27][28][29][30] It is important to highlight that oligogenicity here is used in the context of penetrance (the classic all-or-none definition); otherwise, there is little doubt that epistasis is a ubiquitous phenomenon in systems biology. Indeed, it has long been realized that there is no single disease that is 'monogenic' in the strict sense of the word.…”

The role of primary cilia in the development and disease of the retina

“…140 Many BBS proteins have been shown to localize to the photoreceptors, [140][141][142][143] and loss of most of the BBSome proteins leads to retinal degeneration in model organisms and humans as part of the multi-organ condition Bardet-Biedl syndrome (BBS). 141,[144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159] For example, Bbs1 knock-in mutant mice develop disorganized OS, and exhibit degeneration of IS and OS. 160 Other work has exemplified the disease mechanism of disrupted trafficking that underlies the retinal degeneration in this ciliopathy.…”