Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly

Abstract

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.

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

“…However, due to a lack of awareness for genetic counseling, there is still a considerable percentage of Chinese people affected by this disease, especially in hereditary PPD pedigrees, and most affected individuals have already missed the optimal treatment time [Wang et al, 2007;Li et al, 2009]. Considering the current status, it will be an important task for genetic counselors to make the populace realize the necessity of counseling.…”

The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis

“…Other limb-specific cis-regulatory elements of SHH are likely, as numerous PPD families with linkage at 7q36 do not present with ZRS alteration. 8,9 The identification of a 4-6 kb deletion between ZRS and SHH in acheiropodia, which phenotype is consistent with the loss of SHH expression in the developing limb, is a further clue.…”

“…Some of these have already been described and studied in PPD families. 8,9 Sequencing of these regions in one individual affected with PPDhypertrichosis (IV-21) revealed no pathogenic variant.…”

“…The existence of other cis-regulatory elements of SHH specific for limb development is likely, as numerous PPD families linked to the 7q36 region do not have a ZRS alteration. 8,9 We studied a large family affected with autosomal dominant PPD. Limb malformations were associated with hypertrichosis affecting the upper back.…”

Mutation analysis of a Chinese pedigree with triphalangeal thumb-polysyndactyly syndrome

“…Moreover, a family consisting of a father with TPTPS and a daughter with tibial hemimeliapolysyndactyly-triphalangeal thumb syndrome was reported (Kantaputra and Chalidapong, 2000). Numerous TPTPS families have no detected mutation or duplication in ZRS, but the symptoms are strongly that linked to the ZRS (Lettice et al, 2003;Gurnett et al, 2007;Li et al, 2009). These findings suggest there is no correlation between phenotypic severity and the extent of duplication or the type of mutation.…”