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.
- Bardet–Biedl syndrome
- homozygosity mapping
- mutation analysis
- molecular genetics
- vision research
- renal medicine
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HMH and SH contributed equally to this work.
Funding This work was supported by grants to FH from the National Institutes of Health (NIH grants DK068306, DK064614, DK069274 and HD045345), grant R01HD04260 from the National Institute of Child Health and Development (NK), R01DK072301 and R01DK075972 (NK) and National Research Service Awards fellowship F32 DK079541 (EED) from the National Institute of Diabetes and Digestive and Kidney Diseases, the Macular Vision Research Foundation (NK), the Foundation for Fighting Blindness (NK), and by grants from NEWLIFE and Wellcome Trust (PB). NK is a Brumley endowed Professor. FH is an investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist and a Frederick GL Huetwell Professor. Other funders: NIH; Howard Hughes Medical Institute.
Competing interests None.
Ethical approval This study was conducted with the approval of the internal review boards of the University of Michigan, the ethics committee of the UCL Institute of Child Health and the internal review board of the Johns Hopkins University.
Provenance and peer review Not commissioned; externally peer reviewed.