Cis‐Regulatory Mutations in Human Disease

Abstract Enhancers are cis‐regulatory elements that accurately control the spatiotemporal pattern of gene expression and these can function over large genomic distances to activate the target gene. Genomewide methodologies have revealed general chromatin signatures for enhancers and the human and mouse noncoding genomes have undergone an extensive functional annotation. An increasing number of enhancer mutations are showing association with human disease, and disease mechanisms are being described that result from altered gene expression. Owing to the modular nature of enhancers, mutations can generate disease phenotypes that represent either a subset of the symptoms of coding mutations or due to a change in specificity of enhancer activity, a novel phenotype. Topologically associated domains, also known as TADs , have emerged as a fundamental structural unit to limit enhancer regulatory activity and disruptions of these boundaries result in gene misexpression and disease. Key Concepts Enhancers function over large genomic distances to activate the target gene. Methodologies have been developed to annotate the functional elements in the noncoding genome. Mutations in enhancers that regulate developmental gene expression can cause congenital abnormalities. Owing to the modular nature of enhancers the disease presentation may be different from mutations in the coding region of the target gene. Disruption of TAD boundaries can result in gene misexpression and disease.