Conotruncal defects (CTDs) comprise 36% of all congenital heart defects and carry significant morbidity. Although their etiology is poorly defined, data suggest that complex genetic mechanisms contribute to their etiology. This Program will define the genetic basis of CTDs. Molecular evaluation of genetic syndromes with CTDs have provided valuable insight into their genetic basis. In particular, studies on the 22q11.2 deletion syndrome defined a large CTD population, identified genes (e.g. TBX1) and developmental pathways contributing to cardiac development and disease. To continue this work, Project 1 will identify genetic modifiers of CTDs in an exceptional, large 22q11.2 deleted patient cohort using genome wide approaches. In Project 2, genome wide studies in a unique, large non-syndromic patient CTD cohort will be completed to identify both case (inherited) and maternal genetic effects. Discoveries made in one patient cohort will be examined for significance in the other. Mouse models based on 22q11 DS will be used to elucidate developmental pathways critical to conotruncal morphogenesis. Genes and developmental pathways described in the mouse models will be examined for disease associated genetic variants in each of the two patient cohorts, and discoveries in Projects 1 and 2 will in turn be examined in the mouse for expression pattern and placement in key developmental pathways. Candidate genes from these studies will be subject to deep sequencing to identify the full range of disease related genetic variants. The proposed studies are highly interactive, leverage unique patient cohorts and mouse models, build upon long standing collaborations, and test the hypotheses that: (1) the 22q11.2 deleted cohort will serve to unmask genetic risk factors for the characteristic cardiac defects, (2) these risk factors apply to the non-syndromic cardiac cohort, and (3) critical developmental pathways can be elucidated in the mouse whose gene members are disease- related in humans. These studies wilt greatly expand our understanding of the genetic basis of CTDs, and will promote the development of novel therapeutic and preventive strategies.

Public Health Relevance

The goal of this project is to understand the genetic causes of congenital heart defects. Project 1 is to find genetic modifiers of heart defects in 22q11 DS. Project 2 is to find genetic risk factors for non-syndromic conotruncal heart defects and Project 3 will use mouse models to help determine which of the candidates identified in Projects 1 and 2 function in cardiac development.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-Y (50))
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Javois, Lorette Claire
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Albert Einstein College of Medicine
Schools of Medicine
United States
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Mlynarski, Elisabeth E; Xie, Michael; Taylor, Deanne et al. (2016) Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome. Hum Genet 135:273-85
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