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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01HL098153-03S1
Application #
8432355
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S2))
Program Officer
Kaltman, Jonathan R
Project Start
2009-09-30
Project End
2015-07-31
Budget Start
2012-03-08
Budget End
2012-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$60,998
Indirect Cost
$24,581
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Manheimer, Kathryn B; Patel, Nihir; Richter, Felix et al. (2018) Robust identification of deletions in exome and genome sequence data based on clustering of Mendelian errors. Hum Mutat 39:870-881
Mercer-Rosa, Laura; Elci, Okan U; Pinto, Nelangi M et al. (2018) 22q11.2 Deletion Status and Perioperative Outcomes for Tetralogy of Fallot with Pulmonary Atresia and Multiple Aortopulmonary Collateral Vessels. Pediatr Cardiol 39:906-910
Manheimer, Kathryn B; Richter, Felix; Edelmann, Lisa J et al. (2018) Robust identification of mosaic variants in congenital heart disease. Hum Genet 137:183-193
Shaaban, Sherin; MacKinnon, Sarah; Andrews, Caroline et al. (2018) Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect. Invest Ophthalmol Vis Sci 59:4054-4064
Mercer-Rosa, Laura; Zhang, Xuemei; Tanel, Ronn E et al. (2018) Perioperative Factors Influence the Long-Term Outcomes of Children and Adolescents with Repaired Tetralogy of Fallot. Pediatr Cardiol :
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
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
Hoang, Thanh T; Marengo, Lisa K; Mitchell, Laura E et al. (2017) Original Findings and Updated Meta-Analysis for the Association Between Maternal Diabetes and Risk for Congenital Heart Disease Phenotypes. Am J Epidemiol 186:118-128
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

Showing the most recent 10 out of 19 publications