Molecular Genetics of Human Congenital Limb Malformations

Abstract Congenital limb malformations are observed in approximately 1 in 500 people making them one of the most frequent birth defects. Increasing numbers of genes are being identified that when functionally perturbed result in human limb abnormalities. The functions of many of these genes have been investigated in the two main models of limb development – the chick and the mouse. Limb defects are often part of complex syndromes that affect other structures in the body. This reflects the multiple roles that many genes play during embryonic development. Recently, an emerging theme is that the disruption of cis ‐regulatory enhancers controlling expression of important developmental genes can lead to limb‐specific birth defects. Future research focusing on how the human limb develops will increase our understanding of the molecular and genetic basis of congenital defects. Key Concepts: Chick and mouse embryology has contributed to our knowledge of limb development and the basis of human limb defects. Many key patterning genes found in mouse and chick research cause human limb defects when mutated. Limb defects are often part of complex syndromes. Defects which affect only the limb are often caused by disruption of cis ‐regulatory enhancers. Future work on how the human limb develops will further our understanding of congenital defects.