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Interrogating the Functional Impact of Regulatory Sequences in Congenital Heart Disease

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Technical Report,01 Jul 2018,30 Jun 2019

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University of Texas Southwestern Medical Center Dallas United States

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Congenital heart disease CHD affects nearly 1 of all newborns and continues to carry a poor overall prognosis. This failure stems largely from an incomplete knowledge of the underlying pathogenetic mechanisms. Thus, there is a critical need to obtain a comprehensive understanding of the genetic factors that disrupt cardiac development and lead to human CHD. Despite considerable progress, most genetic contributors to CHD remain unknown. Here, we propose a novel strategy to annotate the remaining dark matter in the genome to potentially identify a key source of the missing heritability that limits the scope of current diagnostic testing. Previous GWAS on patients with CHD identified common variants in the loci of 17 different genes linked to congenital abnormalities. Most of these variants are non-coding and lie within a class of regulatory elements called transcriptional enhancers. Given the key role that enhancers play in development, we postulate that enhancer variants cause cardiac developmental defects that contribute significantly to CHD. But direct evidence to support this notion is lacking. Therefore, we will test our central hypothesis that specific enhancers are required for cardiac development. The objective of this proposal is to develop a robust enhancer annotation pipeline for human cardiac development that we can use to rigorously evaluate our central hypothesis. Our rationale is that attainment of our objective will prioritize enhancers for causative association with human CHD in future proposals.

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  • Medicine and Medical Research
  • Anatomy and Physiology

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