Abundant evidence indicates a genetic contribution to congenital heart disease (CHD), but the specific genes responsible for most CHD are still unknown. Previously identified CHD mutations have been found in family-based investigations. However, most CHD arises as an unexpected and unexplained event, likely due to incomplete penetrance of some gene variants and impaired reproductive fitness associated with others. This is particularly true for severe CHD which, if untreated, causes early lethality. In this application, we propose to focus on sporadic rather than familial CHD. Subjects will have severe CHD defined as cyanotic lesions and others that usually require intervention in infancy. Based on evidence that abnormal dosage of critical developmental genes causes some CHD, we will conduct genome-wide analyses for de novo copy number variants in trios of the affected child and unaffected parents. We will also assess alleles that contribute to severe CHD through case-control whole genome association studies. We will determine whether somatic mutations account for some sporadic, severe CHD and will analyze gene transcription in human malformed hearts. Together our studies will assess the contribution of previously defined CHD genes, identify new loci, genes, mutations and mechanisms, and evaluate genotype-phenotype relationships. Our studies harness modern genomic approaches and will use novel sequencing and transcription profiling strategies. We anticipate these investigations will foster highly productive collaborations with other research centers in this Consortium and will contribute fundamental knowledge about human cardiogenesis to the Cardiac Development Consortium. We propose four specific aims: 1. Use subgenome capture strategies to interrogate the sequence and copy number of known and candidate CHD genes, as well as newly identified CHD genes, and assess genotype-phenotype correlations. 2. Determine if somatic mutations cause or modulate CHD. 3. Define novel severe CHD loci (by discovery of de novo copy number variants and by genome-wide association studies), genes, and mutations. 4. Define RNA expression in affected regions of malformed human hearts. Three cores will support these studies: an Imaging Core for Complex CHD Phenotyping, a Genomic Analyses Core, and a Sequence Analysis Core.

Public Health Relevance

Our studies will define new genes and mutations that cause severe CHD, enable genotype-phenotype studies, provide a framework to study the relationship of genetic factors to long-term outcomes, and provide data on recurrence risks. Data from the proposed studies, as well as our faculty, clinical and genetics resources, will advance the goals of the NHLBl's Pediatric Cardiovascular Translation Consortium.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1-CSR-B (S2))
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Kaltman, Jonathan R
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Children's Hospital Boston
United States
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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
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
Glessner, Joseph T; Bick, Alexander G; Ito, Kaoru et al. (2014) Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ Res 115:884-896
Fahed, Akl C; Gelb, Bruce D; Seidman, J G et al. (2013) Genetics of congenital heart disease: the glass half empty. Circ Res 112:707-20
Pediatric Cardiac Genomics Consortium; Gelb, Bruce; Brueckner, Martina et al. (2013) The Congenital Heart Disease Genetic Network Study: rationale, design, and early results. Circ Res 112:698-706
Zaidi, Samir; Choi, Murim; Wakimoto, Hiroko et al. (2013) De novo mutations in histone-modifying genes in congenital heart disease. Nature 498:220-3
Gelb, Bruce D; Seidman, Christine E (2012) The Good SHP2 Association: a porthole into the genetics of congenital heart disease. Circ Cardiovasc Genet 5:271-3

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