Gene Mapping Of Congenital Preaxial Polydactyly In A Chinese Family

Preaxial polydactyly(PPD)is one of the most frequently observed human limb developmental disorders.Polydactyly can occur either as an isolated disorder or as a part of a syndrome and can be classified into preaxial polydactyly and postaxial polydactyly according to its anatomical location.Preaxial polydactyly(PPD)refers to an excess of parts on the radial side of the limb.According to the classification method of Temtamy and Mckusick,Preaxial polydactyly can be divided into four types:typeⅠ(PPD-Ⅰ)is the duplication of one or more of the skeletal components of a biphalangeal thumb;typeⅡ(PPD-Ⅱ)is the polydactyly of a triphalangeal thumb;typeⅢ(PPD-Ⅲ)is the polydactyly of an index finger;typeⅣ(PPD-Ⅳ)is the polysyndactyly.Preaxial polydactyly is usually caused by single gene mutation and shows an autosomal-dominant mode of inheritance.The phenotype shows varation within families and range from a simple addition of a phalanx in triphalangeal thumb to whole digit duplication.Six associated mutations have been discovered in Several European and American families.All of them locate in ZRS(ZPA regulatory sequence)of chromosome 7q36.Research had been performed on a Chinese pedigree of congenital preaxial polydactyly through genescan and linkage analysis to investigate the location of the disease-causing loci associated with the family,we screened the candidate regions by directly sequencing,including the whole 17 exons of LMBR1 gene and the regulatory element(ZRS)of SHH.We had identified a six generations pedigree of autosomal dominant congenital preaxial polydactyly came from Zhejiang province.Genomic DNA was extracted from peripheral blood samples of 21 affected and 24 unaffected family members.9 microsatellite markers on chromosome 7q36 were used as genetic markers and were by PCR(polymerase chain reaction)with fluorescence labeled primers.Genome screening and genotyping were conducted by ABI377 DNA sequencer in this PPDⅡ/Ⅲfamily and linkage analysis was performed with LINKAGE software package.The exons of LMBR1 and ZRS were amplified by PCR,then sequenced by ABI3700 sequencer.All affected members of this preaxial polydactyly family share certain haplotypes,and differ with the reported foreigners.A maximum two-point LOD score (Zmax)of 7.822 was obtained at recombination fraction(θ)0.00 for marker HING1, which implied strong linkage between PPD phenotype of this kindred and chromosome 7q36.Haplotype construction and recombination analysis narrowed the candidate region for PPDⅡ/Ⅲto a 1.7cM region between D7S2465 and D7S2423, which covered the previous reported 450-kb interval.We found a G/C SNP in ZRS,but did not detect any pathogenic mutation loci located in LMBR1 exons or ZRS responsible for this pedigree.Our results implied that the pathogeny mutation in this Chinese preaxial polydactylyⅡ/Ⅲpedigree doesn't exist in the reported region,which showed the genetic heterogeneous of PPD.