Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene.
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.
Nishimura
Darryl Y
DY
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Swiderski
Ruth E
RE
Searby
Charles C
CC
Berg
Erik M
EM
Ferguson
Amanda L
AL
Hennekam
Raoul
R
Merin
Saul
S
Weleber
Richard G
RG
Biesecker
Leslie G
LG
Stone
Edwin M
EM
Sheffield
Val C
VC
D000483:Alleles; D020087:Alu Elements; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D019295:Computational Biology; D003241:Consanguinity; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D005808:Genes, Recessive; D023281:Genomics; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
C472639:BBS9 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins