Genetics of clubfoot; recent progress and future perspectives

Clubfoot or talipes equinovarus (TEV) is an inborn three-dimensional deformity of leg, ankle and foot. It results from structural defects of several tissues of foot and lower leg leading to abnormal positioning of foot and ankle joints. TEV can lead to long-lasting functional disability, malformation and discomfort if left untreated. Substantial progress has been achieved in the management and diagnosis of limb defects; however, not much is known about the molecular players and signalling pathways underlying TEV disorder. The homeostasis and development of the limb depends on the complex interactions between the lateral plate mesoderm cells and outer ectoderm. These complex interactions include HOX signalling and PITX1-TBX4 pathways. The susceptibility to develop TEV is determined by a number of environmental and genetic factors, although the nature and level of interplay between them remains unclear. Familial occurrence and inter and intra phenotypic variability of TEV is well documented. Variants in genes that code for contractile proteins of skeletal myofibers might play a role in the aetiology of TEV but, to date, no strong candidate genes conferring increased risk have emerged, although variants in TBX4, PITX1, HOXA, HOXC and HOXD clusters genes, NAT2 and others have been shown to be associated with TEV. The mechanisms by which variants in these genes confer risk and the nature of the physical and genetic interaction between them remains to be determined. Elucidation of genetic players and cellular pathways underlying TEV will certainly increase our understanding of the pathophysiology of this deformity.