Clubfoot genetics

Abstract

The clubfoot is one of the most common serious congenital deformities of the musculoskeletal system and presents an incidence of 1/1000 live births. The etiology of the syndromic forms of clubfoot is varied and the causes of isolated clubfoot are not well understood. Modern advances in genetics have allowed researchers to begin to identify the complex etiology of clubfoot. Several recent genetic studies have identified a key developmental pathway, the PITX1-TBX4 transcriptional pathway, in the etiology of clubfoot. Both PITX1 and TBX4 are uniquely expressed in the hindlimb, which helps explain the phenotype of the foot seen with mutations in these transcription factors. However, other studies also identified a 2.2 Mb microduplication on chromosome 17q23.1q23.2 which includes T-box 4 (TBX4), and another 16 genes in 3 of 66 families reported as non-syndromic clubfoot; Where minimal evidence was found for an association between TBX4 and clubfoot and no pathogen sequence variants were identified in the two known TBX4 hindlimb enhancer elements. Altogether, these results demonstrate that variation in and around the TBX4 gene and the 17q23.1q23.2 microduplication are not a frequent cause of this common orthopedic birth defect and narrows the 17q23.1q23.2 nonsyndromic clubfoot-associated region.