Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes

Bardet-Biedl syndrome (BBS; MIM 209900) is a genetically heterogeneous autosomal recessive disorder characterized by progressive retinal degeneration, truncal obesity, cognitive impairment, polydactyly, hypogonadism, and renal anomalies.1–6 Among the nonconsanguineous populations of Northern Europe and America, the prevalence ranges from 1 in 100,000 in North America7 to 1 in 160,000 in Switzerland.8 BBS incidence increases within populations of high consanguinity or those that are geographically isolated.4,9,10 To date, 15 genes (BBS112, Meckel syndrome 1 [MKS1, BBS13], centrosomal protein 290 kDa/nephronophthisis 6 [CEP290/NPHP6, BBS14], and C2ORF86 [BBS15]) have been implicated in BBS.11,12 Mutations in these genes account only for approximately 70% of BBS patients, suggesting that there are additional genes to be found for BBS.13BBS1 and BBS10 are major pathogenic genes in European populations, each accounting for at least 20% of cases in most series.14,15 However, most other genes are rare contributors. For example, there is only a single documented family with mutations in each of BBS11 (TRIM32), BBS13 (MKS1), BBS14 (CEP290), and BBS15 (C2ORF86).12,16,17 A number of recent publications have expanded the spectrum of known BBS mutations,18–21 and suggested that mutations in some genes, including BBS13 and TMEM67/MKS3, can modify the expression of BBS phenotypes in patients who have mutations in other genes. BBS is also characterized by profound interfamilial and intrafamilial clinical variability, which is possibly explained in part by the presence of second-site modifiers. In some families, three mutated alleles in two BBS genes have been implicated (triallelic inheritance). BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS7, BBS8, and BBS10 have been implicated in triallelic inheritance of BBS,22–25 but the specific contribution of each allele is difficult to ascertain. Moreover, it has been suggested that there might be a connection between triallelism and the phenotypic severity of the disease.26 However, some studies have not identified a complex inheritance mode in this syndrome.27,28 In this study, we analyzed 55 families for known BBS genes (BBS1-BBS15) and identified 43 mutations in 46 families, 21 of which are novel. We also identified 7 Caucasian, 1 Arabic, and 1 Tunisian family in whom the molecular genetic findings raised the possibility of triallelic inheritance involving BBS1, BBS2, BBS3, BBS6, BBS7, BBS8, BBS9, BBS10, or BBS12. Although some sequence variations were identified in additional genes, no homozygous potential mutations were identified in previously unidentified BBS genes.