Cis-Regulatory Enhancer Mutations are a Cause of Human Limb Malformations

Abstract

Congenital limb malformations are the second most common class of human birth defects and can be caused both by environmental and genetic factors. While it is known that some limb malformations are the result of coding mutations that disrupt genes, identifying the causal mutation in a patient with an isolated limb malformation is often difficult. This may be due in part to the growing number of cases with isolated limb malformations that are shown to be the result of nucleotide changes in gene regulatory elements. These regulatory mutations affect gene expression in the developing limb and can cause dramatic changes to patterning, leading to congenital limb malformations. In this chapter, we will review characterized gene regulatory mutations leading to human limb malformations and also provide evidence that additional limb enhancers could be the cause of other human limb malformations.