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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD070454-03
Application #
8499057
Study Section
Special Emphasis Panel (ZHD1-DSR-Y (50))
Program Officer
Javois, Lorette Claire
Project Start
2011-09-24
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$1,229,041
Indirect Cost
$226,982
Name
Albert Einstein College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Werner, Petra; Latney, Brande; Deardorff, Matthew A et al. (2016) MESP1 Mutations in Patients with Congenital Heart Defects. Hum Mutat 37:308-14
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
Hestand, Matthew S; Nowakowska, Beata A; Vergaelen, Elfi et al. (2016) A catalog of hemizygous variation in 127 22q11 deletion patients. Hum Genome Var 3:15065
Guo, Tingwei; Chung, Jonathan H; Wang, Tao et al. (2015) Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome. Am J Hum Genet 97:869-77
Mlynarski, Elisabeth E; Sheridan, Molly B; Xie, Michael et al. (2015) Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome. Am J Hum Genet 96:753-64
McDonald-McGinn, Donna M; Sullivan, Kathleen E; Marino, Bruno et al. (2015) 22q11.2 deletion syndrome. Nat Rev Dis Primers 1:15071
Chung, Jonathan H; Cai, Jinlu; Suskin, Barrie G et al. (2015) Whole-Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations. Hum Mutat 36:797-807
Racedo, Silvia E; McDonald-McGinn, Donna M; Chung, Jonathan H et al. (2015) Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation. Am J Hum Genet 96:235-44
Vorstman, Jacob A S; Breetvelt, Elemi J; Duijff, Sasja N et al. (2015) Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. JAMA Psychiatry 72:377-85
Ramakrishnan, Anushuya; Lee, Laura J; Mitchell, Laura E et al. (2015) Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis. Pediatr Cardiol 36:1442-51

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