Mutational Load in a Series of 140 Bardet Biedl Syndrome Families Mutated in Known BBS Genes (BBS1-BBS12)

Abstract

Purpose: : Bardet-Biedl syndrome (BBS) is characterized by early-onset RP, childhood-onset obesity, polydactyly, hypogonadism, cognitive impairment and kidney dysplasia and is now recognized to be a ciliopathy. Positional cloning studies and subsequent comparative genomic approaches have proven the extensive genetic heterogeneity of this autosomal recessive condition. In some families three mutated alleles in two genes are involved defining oligogenic inheritance. To date 12 genes have been identified: BBS1 to BBS12.We present the mutational load of 140 BBS families for which pathogenic mutations have been found.

Methods: : Mutations were identified by: 1° systematic extensive direct sequencing of the coding sequence of the 12 BBS genes (138 exons or 151 amplicons) in 41% of the families ; 2°guided BBS gene sequencing by way of preliminary SNP analysis or microsatellite analysis for consanguineous or large families (50% of the families); 3° by way of preliminary use of Aspers ophthalmic chip (less then 9% of the families).

Results: : 112 families (80%) carry 2 mutations in the known BBS genes: 31% in BBS10, 25% in BBS1 and 9% in BBS12. 18 families (13%) carry to date only one mutation (9 in BBS1 and the remaining in BBS2, BBS4 and BBS6). 22 new mutations were identified in this study.

Conclusions: : BBS1, BBS10 and BBS12 are the most frequently mutated genes in this cohort (80% of the mutational load). Recurrent mutations were mainly BBS1 M390R (75% of BBS1 mutations); C91fsX BBS10 (41% of BBS10 mutations). More then 50% of the mutations are private. No mutation were found for BBS11. This study shows the difficult task of mutation identification for BBS and the need to establish a efficient strategy for cost-effective gene testing.

Keywords: genetics • retinal degenerations: hereditary • gene screening