Genetics of clubfoot.

Abstract

Modern advances in genetics have allowed investigators to identify the complex etiology of clubfoot. It has become increasingly apparent that clubfoot is a heterogeneous disorder with a polygenetic threshold model explaining its inheritance patterns. Several recent genetic studies have identified a key developmental pathway, the PITX1-TBX4 transcriptional pathway, as being important in clubfoot etiology. Both PITX1 and TBX4 are uniquely expressed in the hindlimb, which helps explain the foot phenotype seen with mutations in these transcription factors. Future studies are needed to develop animal models to determine the exact mechanisms by which these genetic abnormalities cause clubfoot and to test other hypotheses of clubfoot pathogenesis.