TY - JOUR
T1 - Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene
AU - Nishimura, Darryl Y.
AU - Swiderski, Ruth E.
AU - Searby, Charles C.
AU - Berg, Erik M.
AU - Ferguson, Amanda L.
AU - Hennekam, Raoul
AU - Merin, Saul
AU - Weleber, Richard G.
AU - Biesecker, Leslie G.
AU - Stone, Edwin M.
AU - Sheffield, Val C.
N1 - Funding Information:
We are grateful to the patients and their families for participating in this study. We thank M. Andrews, G. Beck, K. Bugge, T. Kucaba, R. Mullins, A. Nalley, and M. Olvera, for technical assistance, and D. Aguiar-Crouch, for administrative assistance. This work was supported by the following grants and organizations: National Institutes of Health grants P50-HL-55006 (to V.C.S.) and R01-EY-11298 (to V.C.S. and E.M.S.); Carver Endowment for Molecular Ophthalmology (to E.M.S. and V.C.S.); Research to Prevent Blindness (to the Department of Ophthalmology, University of Iowa); the University of Iowa (to D.Y.N.); and the intramural program of the National Human Genome Research Institute (to L.G.B.).
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=28144460266&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28144460266&partnerID=8YFLogxK
U2 - 10.1086/498323
DO - 10.1086/498323
M3 - Article
C2 - 16380913
AN - SCOPUS:28144460266
SN - 0002-9297
VL - 77
SP - 1021
EP - 1033
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -