Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene

Darryl Y. Nishimura, Ruth E. Swiderski, Charles C. Searby, Erik M. Berg, Amanda L. Ferguson, Raoul Hennekam, Saul Merin, Richard Weleber, Leslie G. Biesecker, Edwin M. Stone, Val C. Sheffield

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Abstract

Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Eight BBS genes representing all known mapped loci have been identified. Mutation analysis of the known BBS genes in BBS patients indicate that additional BBS genes exist and/or that unidentified mutations exist in the known genes. To identify new BBS genes, we performed homozygosity mapping of small, consanguineous BBS pedigrees, using moderately dense SNP arrays. A bioinformatics approach combining comparative genomic analysis and gene expression studies of a BBS-knockout mouse model was used to prioritize BBS candidate genes within the newly identified loci for mutation screening. By use of this strategy, parathyroid hormone-responsive gene B1 (B1) was found to be a novel BBS gene (BBS9), supported by the identification of homozygous mutations in BBS patients. The identification of BBS9 illustrates the power of using a combination of comparative genomic analysis, gene expression studies, and homozygosity mapping with SNP arrays in small, consanguineous families for the identification of rare autosomal recessive disorders. We also demonstrate that small, consanguineous families are useful in identifying intragenic deletions. This type of mutation is likely to be underreported because of the difficulty of deletion detection in the heterozygous state by the mutation screening methods that are used in many studies.

Original languageEnglish (US)
Pages (from-to)1021-1033
Number of pages13
JournalAmerican Journal of Human Genetics
Volume77
Issue number6
DOIs
StatePublished - Dec 2005

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Bardet-Biedl Syndrome
Genomics
Gene Expression
Genes
Mutation
Single Nucleotide Polymorphism
Polydactyly
Learning Disorders
Pedigree
Computational Biology
Parathyroid Hormone
Knockout Mice

ASJC Scopus subject areas

  • Genetics

Cite this

Nishimura, D. Y., Swiderski, R. E., Searby, C. C., Berg, E. M., Ferguson, A. L., Hennekam, R., ... Sheffield, V. C. (2005). Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. American Journal of Human Genetics, 77(6), 1021-1033. https://doi.org/10.1086/498323

Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. / Nishimura, Darryl Y.; Swiderski, Ruth E.; Searby, Charles C.; Berg, Erik M.; Ferguson, Amanda L.; Hennekam, Raoul; Merin, Saul; Weleber, Richard; Biesecker, Leslie G.; Stone, Edwin M.; Sheffield, Val C.

In: American Journal of Human Genetics, Vol. 77, No. 6, 12.2005, p. 1021-1033.

Research output: Contribution to journalArticle

Nishimura, DY, Swiderski, RE, Searby, CC, Berg, EM, Ferguson, AL, Hennekam, R, Merin, S, Weleber, R, Biesecker, LG, Stone, EM & Sheffield, VC 2005, 'Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene', American Journal of Human Genetics, vol. 77, no. 6, pp. 1021-1033. https://doi.org/10.1086/498323
Nishimura DY, Swiderski RE, Searby CC, Berg EM, Ferguson AL, Hennekam R et al. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. American Journal of Human Genetics. 2005 Dec;77(6):1021-1033. https://doi.org/10.1086/498323
Nishimura, Darryl Y. ; Swiderski, Ruth E. ; Searby, Charles C. ; Berg, Erik M. ; Ferguson, Amanda L. ; Hennekam, Raoul ; Merin, Saul ; Weleber, Richard ; Biesecker, Leslie G. ; Stone, Edwin M. ; Sheffield, Val C. / Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. In: American Journal of Human Genetics. 2005 ; Vol. 77, No. 6. pp. 1021-1033.
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