Clubfoot (talipes equinovarus) is a congenital malformation affecting muscles, bones, connective tissue and vascular or neurological structures in limbs. It has a complex aetiology, both genetic and environmental. To date, the most important findings in clubfoot genetics involve PITX1 variants, which were linked to clubfoot phenotype in mice and humans. Additionally, copy number variations encompassing TBX4 or single nucleotide variants in HOXC11, the molecular targets of the PITX1 transcription factor, were linked to the clubfoot phenotype. In general, genes of cytoskeleton and muscle contractile apparatus, as well as components of the extracellular matrix and connective tissue, are frequently linked with clubfoot aetiology. Last but not least, an equally important element, that brings us closer to a better understanding of the clubfoot genotype/phenotype correlation, are studies on the two known animal models of clubfoot—the pma or EphA4 mice. This review will summarise the current state of knowledge of the molecular basis of this congenital malformation.
- genetic research
- human genetics
- and neonatal diseases and abnormalities
- genetic predisposition to disease
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Contributors EH-K was responsible for drafting, writing the manuscript, preparing the figures, tables and corrections. KN was responsible for drafting, writing, preparing the tables and corrections. AJ was responsible for writing and corrections. PT was responsible for drafting, writing and corrections.
Funding This work was supported by the Polish National Science Centre (2017/27/N/NZ5/02940 to EHK). AJ was supported by a grant from the Polish National Science Centre (2016/22/E/NZ5/00270).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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