Mutation screening of muscle development genes in patients with idiopathic clubfoot

Background: Congenital idiopathic clubfoot is a very common musculoskeletal birth defect, but with no known etiology. Dietz et al. have shown possible linkage in chromosome 3 and 13 in a large, multigenerational family with congenital idiopathic clubfoot. Current evidence suggests that muscle development is impaired in patients with congenital idiopathic clubfoot, therefore we hypothesized that mutations in genes related to muscle development could be associated with this deformity. From the areas identified in the linkage study, candidate genes SPRY2, RAF1, IQSEC1, LMO7, and UCHL3 were selected based upon their presence in skeletal muscle as well as their involvement in muscle development. Methods: The exons and splice sites of the five genes were screened via sequence-based analysis in a group of 24 patients with congenital idiopathic clubfoot. All single nucleotide polymorphisms (SNPs) found were compared to public databases to determine allelic frequency and amino acid modification. Results: While many SNPs were found, none proved to be significantly associated with the phenotype of congenital idiopathic clubfoot. The SNPs found were shown to be common amongst a non-clubfoot population and to follow the allelic frequency of the general population. Conclusions: Based upon these results, SPRY2, RAF1, IQSEC1, LMO7, and UCHL3 are not likely to be the major causes of congenital idiopathic clubfoot. Given the complexity of myogenesis, many other candidate genes remain that could cause defects in the hypaxial musculature that is invariably observed in congenital idiopathic clubfoot. Clinical Relevance: This study further identifies genes which are unlikely to be the direct cause of congenital idiopathic clubfoot. It also helps to eliminate suspected genes found within the given bounds of chromosome 3 and 13.