Submitted to: Journal of Pediatric Orthopaedics
Publication Type: Peer reviewed journal
Publication Acceptance Date: 8/10/2005
Publication Date: 9/20/2005
Citation: Heck, A.L., Bray, M.S., Scott, A., Blanton, S.H., Hecht, J.T. 2005. Variation in CASP10 gene is associated with idiopathic talipes equinovarus. Journal of Pediatric Orthopaedics. 25(5):598-602. Interpretive Summary: Clubfoot is a developmental defect characterized by loss of flexibility in the lower leg and an angled and/or inverted foot. This common birth defect is treatable, but the factors that lead to the development of clubfoot are largely unknown. We proposed that variation in the DNA sequence of three genes, caspase 8 (CASP8), caspase 10 (CASP10), and CASP8 and FADD-like apoptosis regulator (CFLAR), might be important during growth and development of the foot. We characterized DNA sequence variants throughout these genes in a set of families with at least one child with clubfoot. We found a DNA sequence variant in CASP10 is associated with clubfoot in white and Hispanic families. This study is the first to find evidence for a candidate gene for clubfoot and provides a scientific foundation to further explore the contributions of other genes in the development of clubfoot.
Technical Abstract: Idiopathic talipes equinovarus (ITEV), more commonly known as clubfoot, is a developmental deformity characterized by rigid ankle equinus, hindfoot varus, and forefoot adduction. This common birth defect is treatable, but the etiology of ITEV is largely unknown. Recently, a deletion in the chromosomal region 2q31-33 was found to be associated with clubfoot. Microsatellite markers spanning the region were genotyped in 57 multiplex ITEV families and 83 simplex trios. Family-based analysis revealed that two microsatellite markers, GATA149B10 and D2S1371, were associated with ITEV in the simplex trios. The 6cM region between the two markers contained the candidate genes CASP8, CASP10, and CFLAR. These genes encode proteins that are regulators of apoptosis, which is important during growth and development. Genotyping of SNPs throughout the genes in this sample of ITEV families has revealed positive linkage with association to the major allele of a variant in CASP10 in simplex ITEV white and Hispanic trios. This study is the first to find evidence for a candidate gene for ITEV and provides a scientific foundation to further explore the contributions of other apoptotic genes in the etiology of clubfoot.