Genetics of clubfoot; recent progress and future perspectives

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.