# Integrative Genomic Analysis of Congenital Heart Disease

> **NIH NIH R00** · WASHINGTON UNIVERSITY · 2021 · $243,394

## Abstract

Project Summary/Abstract
My goal is to become an independent investigator in human genetics focusing on understanding the molecular
basis of cardiovascular (CV) diseases such as congenital heart disease (CHD). CHD affects ~1% of live births,
and there are now more adults with CHD than children. Although CHD has a strong genetic component, the
causative mechanisms remain poorly understood. As part of the Pediatric Cardiac Genomics Consortium
(PCGC), we have performed whole exome sequencing (WES) on 3,443 case trios from > 13,000 patients
recruited into the study. We found that de novo mutations (DNMs) underlie 10% of cases and rare inherited
mutations contribute to ~1.8% of cases. Together with environmental risk factors, copy number variation, and
aneuploidy, these findings only explain ~45% of CHD. My central hypothesis is that a subset of CHD cases
result from the epistatic interaction of rare and common variants in the same biological pathway and that
polygenic inheritance can account for some proportion of unexplained CHD cases. Moreover, I hypothesize
that a combined analysis of de novo and transmitted variations has enhanced power to identify additional CHD
risk genes. I propose three aims that will utilize my background in statistical genetics to CHD genetics. In Aim
1, I will identify genetic modifiers of FLT4, a gene we have shown that loss of function mutations cause 2.3% of
Tetralogy of Fallot, albeit with striking incomplete penetrance. I will apply a hypothesis-based candidate gene
approach to study how common variants in modifier genes modulate the expressivity of driver mutations in
FLT4 by jointly analyzing WES and SNP array data from ~2,500 European CHD trios. I will then analyze WES
data from 3,443 CHD trios to determine if there is significant transmission disequilibrium for FLT4 missense
mutations. In Aim 2, I will perform an integrated analysis of DNMs, rare inherited variants, and de novo CNVs
to identify additional CHD genes that could not be identified when modeling different types of genetic variants
separately. In Aim 3, I will analyze SNP array and WES data in ~2,500 European CHD trios to investigate the
combined effects of common polygenic variants and DNMs. Further, I will use a genome-wide polygenic risk
score (PRS) method to identify patients with a high PRS equivalent to the risk introduced by a monogenic
pathogenic mutation. In the K99 phase, I will receive training in both genome & structural variation analyses
and cardiac genetics & physiology. Following my K99 training, I will use these techniques to develop
bioinformatics pipelines for the integrated analysis of common polygenic and rare variants in CV diseases as I
transition to independence. This proposal will identify the genetic underpinnings of some proportion of
unexplained cases, allowing new insight into mechanisms governing disease development, and the opportunity
to mitigate these risks. I will distinguish my research from my mentors’ by developing s...

## Key facts

- **NIH application ID:** 10135142
- **Project number:** 5R00HL143036-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sheng Chih Jin
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $243,394
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135142

## Citation

> US National Institutes of Health, RePORTER application 10135142, Integrative Genomic Analysis of Congenital Heart Disease (5R00HL143036-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135142. Licensed CC0.

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