This program will use multiple approaches to identify the genetic basis of a significant subset of congenital heart defects called conotruncal and related heart defects (CTDs). We hypothesize and data suggest that a range of genetic mechanisms contribute to the etiology of these birth defects including SNPs, CNVs and rare variants, and that a multitude of approaches will help identify disease-related variants. To elucidate these mechanisms, in Aim 1 relatively unbiased genome wide analyses will be completed using a large, non- syndromic CTD cohort ascertained over the last 15 years. In particular an exact replication of our successful family-based discovery analyses will be performed, and inherited, de novo and maternal copy number variations (CNVs) that are associated with CTDs will be identified using a case-control design.
Aim 2 a will explore the hypothesis that the 22q11.2 deleted cohort, at-risk for CTDs, will unmask disease-related genes that also pertain to the larger population of non-deleted CTD cases. To test this hypothesis, genetic modifiers of the cardiac phenotype in the 22q11.2 deleted cohort (from Project 1) will be assessed for disease- association in the non-syndromic cohort (with matched CTDs) to replicate findings from the 22q11.2 deleted cohort and identify variants conferring disease risk in the CTD cohort.
Aim 2 b will translate discoveries made in mouse models (Project 3) deciphering the biological underpinnings of conotruncal development via the Tbx1 developmental pathway, into human disease. Genes and genetic pathways defined by the mouse experiments will be assessed for disease-relatedness in the non-syndromic CTD cohort. Finally, in Aim 3 large scale deep sequencing to identify rare and common genetic variants in disease-associated genes/loci identified from Aims 1 and 2 will be performed to identify the range of genetic mechanisms causing non- syndromic CTDs. The proposed studies leverage unique large syndromic and non-syndromic study cohorts to decipher the genetic basis of CTDs and apply both genome wide and candidate gene approaches. The family based model identifies both inherited and novel matemal genetic effects. Deep sequencing of associated and candidate loci will identify both rare and common disease-associated variants.

Public Health Relevance

Congenital heart defects are the most common, serious birth malformation affecting approximately 1 in 200 live births. Despite their prevalence and public health implication, their etiology remains poorly understood. These studies will elucidate the genetic basis for a subset of these malformations so that novel therapeutic and preventive strategies can be designed, and clinical management and outcomes improved.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-Y)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
United States
Zip Code
Kruszka, Paul; Addissie, Yonit A; McGinn, Daniel E et al. (2017) 22q11.2 deletion syndrome in diverse populations. Am J Med Genet A 173:879-888
Guo, Tingwei; Repetto, Gabriela M; McDonald McGinn, Donna M et al. (2017) Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3. Circ Cardiovasc Genet 10:
Racedo, Silvia E; Hasten, Erica; Lin, Mingyan et al. (2017) Reduced dosage of ?-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome. PLoS Genet 13:e1006687
Johnston, H Richard; Chopra, Pankaj; Wingo, Thomas S et al. (2017) PEMapper and PECaller provide a simplified approach to whole-genome sequencing. Proc Natl Acad Sci U S A 114:E1923-E1932
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
Xie, Hongbo M; Werner, Petra; Stambolian, Dwight et al. (2017) Rare copy number variants in patients with congenital conotruncal heart defects. Birth Defects Res 109:271-295
Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754
Guo, Xingyi; Delio, Maria; Haque, Nousin et al. (2016) Variant discovery and breakpoint region prediction for studying the human 22q11.2 deletion using BAC clone and whole genome sequencing analysis. Hum Mol Genet 25:3754-3767
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

Showing the most recent 10 out of 35 publications