Interrogating the functional consequences of genetic diseases due to mutations in chromatin modifiers.

Disrupted genes in Mendelian syndromes have large effects on downstream targets, contributing to the multitude of syndromic features. One or more of these gene targets may affect the risk of common disease (Figure 1). Recent studies have demonstrated a combinatorial effect of Mendelian syndromes on risk of common disease [5, 6], but until recently, with the advent of high throughput sequencing, we have not had the ability to systematically detect these interactions within an individual patient. While the relationship between Mendelian syndromes and common diseases acts through multiple layers of cellular regulation, this proposal represents a focused approach to study interactions at the level of transcriptional regulation. Understanding the joint influence of monogenic mutations and common disease variants on disease phenotypes allows us to unravel the underlying biological processes contributing to human disease.