Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly

• Published in: European journal of human genetics : EJHG 2009-05, Vol.17 (5), p.604-610
• Main Authors: Li, Hui, Wang, Cheng-Ye, Wang, Jia-Xin, Wu, Gui-Sheng, Yu, Ping, Yan, Xiao-Yi, Chen, Yong-Gang, Zhao, Lu-Hang, Zhang, Ya-Ping
• Format: Article
• Language: English
• Subjects: Asian Continental Ancestry Group - genetics; Biochemistry; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Central nervous system; China; Chromosome 7; Chromosome Mapping; Chromosomes, Human, Pair 7 - genetics; Classical genetics, quantitative genetics, hybrids; Cytogenetics; Diseases of the osteoarticular system; DNA Mutational Analysis - methods; Etiology; Family Health; Female; Fingers & toes; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene mapping; General aspects. Genetic counseling; Genetic Linkage; Genetic Predisposition to Disease - genetics; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Haplotypes; Hedgehog protein; Human; Human Genetics; Humans; Laboratories; Lod Score; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Microsatellite Repeats - genetics; Molecular and cellular biology; Mutation; Pedigree; Phenotypes; Polydactyly; Polydactyly - ethnology; Polydactyly - genetics; Polydactyly - pathology; Reptiles & amphibians; Zoology
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2008.240

Mutations in the long-range limb-specific cis -regulator (ZRS) could cause ectopic shh gene expression and are responsible for preaxial polydactyly (PPD). In this study, we analyzed a large Chinese isolated autosomal dominant PPD pedigree. By fine mapping and haplotype construction, we located the linked region to a 1.7 cM interval between flanking markers D7S2465 and D7S2423 of chromosome 7q36. We directly sequenced the candidate loci in this linked region, including the coding regions of the five genes ( HLXB9 , LMBR1 , NOM1 , RNF32 and C7orf13 ), the regulatory element (ZRS) of shh , the whole intron 5 of LMBR1 which contained the ZRS, and 18 conserved noncoding sequences (CNSs). Interestingly, no pathogenic mutation was identified. By using real-time quantitative PCR (qPCR), we also excluded the ZRS duplication in this pedigree. Our results indicate that, at least, it is not the mutation in a functional gene, CNS region or duplication of ZRS that cause the phenotype of this pedigree. The etiology of this PPD family still remains unclear and the question whether another limb-specific regulatory element of shh gene exists in the noncoding region in this 1.7 cM interval remains open for future research.