Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping

Abstract

Bardet-Biedl syndrome (BBS) is a ciliopathy with pleiotropic effect that manifests primarily as renal insufficiency, polydactyly, retinal dystrophy and obesity. The current phenotype-genotype correlation is insufficient to predict the likely causative mutation that makes sequencing of all 14 BBS genes an often necessary but highly complicated way to identify the underlying genetic defect in affected patients. In this study, homozygosity mapping is shown as a robust approach that is highly suited for genetically heterogeneous autosomal recessive disorders in populations in which consanguinity is prevalent. This approach allowed us to quickly identify seven novel mutations in seven families with BBS. Some of these mutations would have been missed by unguided routine sequencing, which suggests that missed mutations in known BBS genes could be more common than previously thought. This study, the largest to date on Saudi BBS families, also revealed interesting phenotypic aspects of BBS, including the first report of non-syndromic retinitis pigmentosa as a novel BBS phenotype.

In search of triallelism in Bardet–Biedl syndrome

“…We have previously reported the first occurrence of nonsyndromic RP in patients with BBS3 mutations so this family with BBS9 mutation (see below) adds to this highly unusual BBS phenotype. 36,38 We note that RP is almost a universal feature of BBS in our cohort with the exception of BBS-F032-A probably because of her young age (2.5 years), as this BBS trait is known to display age-related penetrance. 39 Homozygosity scan is highly effective in the molecular analysis of BBS and can guide the search for cryptic splicing mutations We have previously demonstrated the utility of homozygosity scans in the molecular analysis of genetically heterogeneous disorders in general and BBS in particular.…”

“…36 Table 1 summarizes the clinical features of all the families enrolled in this study (Figure 1). All but one family were consanguineous and all were of Arab origin.…”

“…39 Homozygosity scan is highly effective in the molecular analysis of BBS and can guide the search for cryptic splicing mutations We have previously demonstrated the utility of homozygosity scans in the molecular analysis of genetically heterogeneous disorders in general and BBS in particular. 36,38,40,41 Taking advantage of the consanguineous nature of the study cohort, we prioritized BBS genes for sequencing based on the results of homozygosity mapping. Indeed, with the exception of one non-consanguineous family (BBS-F009), all families had ROH that overlapped with at least one BBS gene, and six of these families were previously reported.…”

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

“…Furthermore, the success we have had in combining autozygome and exome analysis in delineating the genetic architecture of other genetically heterogeneous disorders, for example, Osteogenesis imperfecta, retinal dystrophy, cataract, mitochondrial diseases, Bardet-Biedl syndrome, and Joubert syndrome 26,[28][29][30][31] 33 ), encouraged us to use a similar approach on MKS to not only determine the mutation distribution in known MKS disease genes but to also potentially identify novel candidate disease genes.…”

“…28,29,34 In order to explore the potential of revealing novel disease genes, all cases in which autozygome-guided mutational analysis was negative were exome sequenced. As we have shown previously, autozygome served as an extremely powerful filter of the resulting variants.…”