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Identification of 11 Novel Mutations in 8 BBS Genes by High-Resolution Homozygosity Mapping
  1. Heather M Harville (harville{at}umich.edu)
  1. HHMI and The University of Michigan School of Medicine, United States
    1. Susanne Held
    1. HHMI and The University of Michigan School of Medicine, United States
      1. Anna Diaz-Font
      1. UCL Institute of Child Health, United Kingdom
        1. Erica E Davis
        1. Johns Hopkins University School of Medicine and Duke University Medical Center, United States
          1. Bill H Diplas
          1. Johns Hopkins Univesity School of Medicine, United States
            1. Richard A Lewis
            1. Baylor College of Medicine, United States
              1. Zvi U. Borochowitz
              1. Bnai-Zion Medical Center, Israel
                1. Weibin Zhou
                1. HHMI and The University of Michigan School of Medicine, United States
                  1. Moumita Chaki
                  1. HHMI and The University of Michigan School of Medicine, United States
                    1. Jim MacDonald
                    1. HHMI and The University of Michigan School of Medicine, United States
                      1. Hulya Kayserili
                      1. Istanbul University, Turkey
                        1. Philip L Beales
                        1. UCL Institute of Child Health, United Kingdom
                          1. Nicholas Katsanis
                          1. Johns Hopkins University School of Medicine and Duke University Medical Center, United States
                            1. Edgar Otto
                            1. HHMI and The University of Michigan School of Medicine, United States
                              1. Friedhelm Hildebrandt (fhilde{at}umich.edu)
                              1. HHMI and The University of Michigan School of Medicine, United States

                                Abstract

                                Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterized by rod-cone dystrophy, obesity, hypogonadism, post-axial polydactyly, renal cysts, and other anomalies of the kidney and urinary tract. 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 both the time and cost required to screen all 204 coding exons. Here, we report 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. In a worldwide cohort of 45 families, we identified, via direct exon sequencing, causative homozygous mutations in 20 families. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218). 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.

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