Interrogating the Functional Impact of Regulatory Sequences in Congenital Heart Disease
Abstract
Topic Area: Congenital Heart Disease Congenital heart disease (CHD) affects nearly 1% of all live births. But the underlying genetic basis for CHD remains incompletely understood. What is known is that CHD arises from defects during heart development and that this process is tightly orchestrated by DNA elements called enhancers that are encoded in each person’s genome sequence. We hypothesize that mutations in enhancer sequences alter normal heart development, which ultimately increases the risk of CHD. However, thousands of enhancers have been identified in the developing human heart, and we currently lack the tools to identify which ones are important for heart development and contribute to CHD risk when mutated. By applying a newly developed high-throughput technology in an embryonic stem cell differentiation system, the goal of this pilot project is to test 500 enhancers for their functions in early human heart development. This is an unprecedented number by today’s standards, and this work will enable future efforts to systematically interrogate the >10,000 enhancers found in developing human hearts. We believe that functional annotation of these enhancers, which comprise much of our genome’s “dark matter,” will identify a major source of the “missing heritability” that currently prevents molecular diagnosis of most forms of CHD. Therefore, through comprehensive enhancer analysis, we hope to enable prioritization of developmental enhancers that contribute to CHD. This increased understanding of the genetic factors disrupting normal heart development will be the first step towards transformational improvements in accurate diagnosis, prognostication, and family screening in children with CHD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810161
Entities
People
- Nikhil V Munshi
Organizations
- United States Army
- University of Texas Southwestern Medical Center