Cleft lip and palate is one of the most common craniofacial birth defects and one of the most common of all birth defects. Its high impact on the affected individual, their families, and society provides strong motivation to understand the causes. Initial genetic studies focused on coding regions of genes that are required for normal development of the lip and palate. However, many individuals with cleft lip and palate do not have mutations in these regions, requiring a broader search for mutations. Recent studies have included conserved noncoding sequences that may harbor regulatory elements. In this chapter, we focus on the discovery and characterization of two noncoding DNA variants in the vicinity of two genes that are associated with cleft lip and palate. First, the minor allele for the SNP rs642961 exemplifies the discovery and validation of a common DNA variant that alters the expression of IRF6, a gene that is required for development of both the lip and the palate. Second, a DNA variant in a sequence that is 1.5 Mb away from the SOX9 gene exemplifies the discovery and validation of a long-range enhancer element. This chapter also contains brief discussions of other examples of DNA variants that affect regulatory elements and contribute to an increased risk for cleft lip and palate. We also discuss approaches and resources available to the craniofacial genetics community to accelerate discovery of additional regulatory elements and DNA variants that affect their activity. We end with a discussion of the tantalizing questions that remain to be answered about the regulation of IRF6 expression and how that may account for missing heritability.
Schutte, B. C., Fakhouri, W. D., & Zemke, D. (2012). Regulatory mutations leading to cleft lip and palate. In Gene Regulatory Sequences and Human Disease (Vol. 9781461416838, pp. 95–122). Springer New York. https://doi.org/10.1007/978-1-4614-1683-8_6