Despite remarkable medical and surgical advances, congenital heart defects (CHD) continue to be associated with significant morbidity and early mortality and present a substantial public health concern. However, the etiology of CHD is poorly understood and thus preventive strategies and therapies based on mechanism of disease are few. Evidence suggests that both genetic and environmental factors contribute to the etiology of CHD and it is increasingly apparent that CHD are complex genetic traits where the risk of disease is determined by the combination of multiple genetic factors. Research suggests that genetic factors influence clinical outcome as well. With rapid technological and methodological advances, large scale genomic analyses to identify genetic risk factors in common diseases characterized as complex traits are now possible but require large study cohorts. The establishment of the Pediatric Cardiac Genomics Consortium promises to overcome this last hurdle. This application proposes to perform genome wide studies in a large, related group of CHD, namely conotruncal defects, to identify genetic risk factors for disease. The association of genetic variants (single nucleotide polymorphisms and copy number variants) with the risk of disease will be tested in a discovery cohort, and findings replicated exactly in a replication cohort. Systems analyses to discover disease related pathways will also be performed. In conjunction with pre-existing samples, cases ascertained by the Consortium will allow for full-cohort and subgroup analyses defined by specific diagnoses. Analyses will be followed by deep sequencing of associated genes, CNVs and members of pathways to identify specific disease-related genetic alterations. Finally, analyses exploring the association of genotype with clinical outcome in the subset of cases with tetralogy of Fallot will be performed. The proposed studies provide a relatively unbiased approach to identify novel genetic risk factors for this large group of CHD. In conjunction with discoveries from the Developmental Biology Consortium, these studies will identify novel mechanisms of disease and begin to advance opportunities for the prevention and therapy of CHD and associated morbidities.

Public Health Relevance

Congenital heart defects (CHD) are the most common, major birth defect and continue to be associated with significant life-long morbidities and early mortality. These studies will begin to identify genetic factors for a large subset of CHD whose etiology is otherwise poorly understood. Such discoveries will provide insight into the mechanisms of disease and allow for more strategic preventive and therapeutic health measures.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S2))
Program Officer
Kaltman, Jonathan R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital of Philadelphia
United States
Zip Code
Bhatt, Shivani M; Goldmuntz, Elizabeth; Cassedy, Amy et al. (2017) Quality of Life is Diminished in Patients with Tetralogy of Fallot with Mild Residual Disease: A Comparison of Tetralogy of Fallot and Isolated Valvar Pulmonary Stenosis. Pediatr Cardiol 38:1645-1653
Bhat, Misha; Goldmuntz, Elizabeth; Fogel, Mark A et al. (2017) Longitudinal Validation of the Diastolic to Systolic Time-Velocity Integral Ratio as a Doppler-Derived Measure of Pulmonary Regurgitation in Patients with Repaired Tetralogy of Fallot. Pediatr Cardiol 38:240-246
Jin, Sheng Chih; Homsy, Jason; Zaidi, Samir et al. (2017) Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 49:1593-1601
Agopian, A J; Goldmuntz, Elizabeth; Hakonarson, Hakon et al. (2017) Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects. Circ Cardiovasc Genet 10:e001449
McKean, David M; Homsy, Jason; Wakimoto, Hiroko et al. (2016) Loss of RNA expression and allele-specific expression associated with congenital heart disease. Nat Commun 7:12824
Johnson, Douglas B; Balko, Justin M; Compton, Margaret L et al. (2016) Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 375:1749-1755
O'Byrne, Michael L; Glatz, Andrew C; Mercer-Rosa, Laura et al. (2015) Trends in pulmonary valve replacement in children and adults with tetralogy of fallot. Am J Cardiol 115:118-24
Mercer-Rosa, Laura; Ingall, Eitan; Zhang, Xuemei et al. (2015) The impact of pulmonary insufficiency on the right ventricle: a comparison of isolated valvar pulmonary stenosis and tetralogy of fallot. Pediatr Cardiol 36:796-801
Avitabile, Catherine M; Whitehead, Kevin; Fogel, Mark et al. (2014) Tricuspid annular plane systolic excursion does not correlate with right ventricular ejection fraction in patients with hypoplastic left heart syndrome after Fontan palliation. Pediatr Cardiol 35:1253-8
Backenroth, Daniel; Homsy, Jason; Murillo, Laura R et al. (2014) CANOES: detecting rare copy number variants from whole exome sequencing data. Nucleic Acids Res 42:e97

Showing the most recent 10 out of 13 publications