Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping

H. M. Harville, S. Held, A. Diaz-Font, E. E. Davis, B. H. Diplas, R. A. Lewis, Z. U. Borochowitz, W. Zhou, M. Chaki, J. MacDonald, H. Kayserili, P. L. Beales, N. Katsanis, E. Otto, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)262-267
Number of pages6
JournalJournal of Medical Genetics
Volume47
Issue number4
DOIs
StatePublished - Apr 2010

Fingerprint

Bardet-Biedl Syndrome
Mutation
Genes
Genetic Heterogeneity
Molecular Biology
Exons
Kidney
Genetic Loci
Retinitis Pigmentosa
Urinary Tract
Cysts
Obesity
Genome
Costs and Cost Analysis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Harville, H. M., Held, S., Diaz-Font, A., Davis, E. E., Diplas, B. H., Lewis, R. A., ... Hildebrandt, F. (2010). Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. Journal of Medical Genetics, 47(4), 262-267. https://doi.org/10.1136/jmg.2009.071365

Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. / Harville, H. M.; Held, S.; Diaz-Font, A.; Davis, E. E.; Diplas, B. H.; Lewis, R. A.; Borochowitz, Z. U.; Zhou, W.; Chaki, M.; MacDonald, J.; Kayserili, H.; Beales, P. L.; Katsanis, N.; Otto, E.; Hildebrandt, Friedhelm.

In: Journal of Medical Genetics, Vol. 47, No. 4, 04.2010, p. 262-267.

Research output: Contribution to journalArticle

Harville, HM, Held, S, Diaz-Font, A, Davis, EE, Diplas, BH, Lewis, RA, Borochowitz, ZU, Zhou, W, Chaki, M, MacDonald, J, Kayserili, H, Beales, PL, Katsanis, N, Otto, E & Hildebrandt, F 2010, 'Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping', Journal of Medical Genetics, vol. 47, no. 4, pp. 262-267. https://doi.org/10.1136/jmg.2009.071365
Harville, H. M. ; Held, S. ; Diaz-Font, A. ; Davis, E. E. ; Diplas, B. H. ; Lewis, R. A. ; Borochowitz, Z. U. ; Zhou, W. ; Chaki, M. ; MacDonald, J. ; Kayserili, H. ; Beales, P. L. ; Katsanis, N. ; Otto, E. ; Hildebrandt, Friedhelm. / Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. In: Journal of Medical Genetics. 2010 ; Vol. 47, No. 4. pp. 262-267.
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AU - Davis, E. E.

AU - Diplas, B. H.

AU - Lewis, R. A.

AU - Borochowitz, Z. U.

AU - Zhou, W.

AU - Chaki, M.

AU - MacDonald, J.

AU - Kayserili, H.

AU - Beales, P. L.

AU - Katsanis, N.

AU - Otto, E.

AU - Hildebrandt, Friedhelm

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N2 - 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.

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