Congenital heart disease is the most common serious birth defect, affecting .8% of live born infants, and ample evidence in both humans and animal model systems supports a genetic basis for CHD. However, low recurrence rates, small sample size and limitation in genomic technology have provided a significant hurdle in defining the genetics of CHD. The goal of this proposal is to combine the state-of-the art genomic technology in the Lifton laboratory with the understanding of the developmental mechanism underlying CHD developed in the Brueckner laboratory to determine the genetic determinants of two types of CHD, Heterotaxy (Htx) and Aortic Arch Abnormalities (AAAs). We have used copy number variation (CNV) analysis in a pilot study of 288 patients with Htx and identified rare genie CNVs in -20%. Interestingly, the CNVs direct attention to novel candidate genes that cluster in 3 pathways previously identified to have a role in the development of LR asymmetry and vasculature: ciliary structure and function, TGF-P signaling and glycosylation. These observations suggest that by combining powerful genomic techniques and large patient cohorts with our understanding of the developmental pathways implicated in cardiac morphogenesis we will identify a genetic cause in a significant number of CHD patients.
In Specific Aim 1, we will recruit and carefully phenotype >2,000 pts with all CHD from Yale, University of Rochester and University College London to share with the PCGC consortium.
In Specific Aim 2, patients from the consortium with Htx and AAAs will first be analyzed for CNVs. Subsequently, sporadic Htx and AAA patients with no detectable copy-number changes can undergo whole exome sequencing to discover causative mutations.
In Specific Aim 3, we will determine whether discrete genotype variants with shared, clinically defined Htx and AAA phenotypes have significantly different short and mid-term clinical outcomes. Here we will focus on three aspects of clinical outcome that have possible links to the causative developmental pathways: myocardial function and renal function, both of which have been associated with ciliary function in model animal systems, and aortic root size, which is prominently affected by TGF-beta signaling in mice and humans.
Although a genetic etiology for congenital heart disease (CHD) has long been suspected, limitations in patient number, genomic technology and understanding of the biology governing heart development have hampered identification of generic causes of CHD. This proposal seeks to use state-of-the-art genomic technology to identify the cause of two types of major CHD, heterotaxy and aortic arch abnormalities.
|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|
|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|
|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|
|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|
|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|
|Zaidi, Samir; Choi, Murim; Wakimoto, Hiroko et al. (2013) De novo mutations in histone-modifying genes in congenital heart disease. Nature 498:220-3|
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