Background: Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterised by the five cardinal features retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity and hypogenitalism. In addition, renal cysts and other anomalies of the kidney and urinary tract can be present. To date, mutations in 12 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of the time and cost required to screen all 204 coding exons.
Method: Here, the use of genome-wide homozygosity mapping as a tool to identify homozygous segments at known BBS loci, in BBS individuals from inbred and outbred background, is reported.
Results: In a worldwide cohort of 45 families, causative homozygous mutations in 20 families were identified via direct exon sequencing. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218).
Conclusions: Thus, in the presence of extreme genetic locus heterogeneity, homozygosity mapping provides a valuable approach to the molecular genetic diagnosis of BBS and will facilitate the discovery of novel pathogenic mutations.