We seek to collaborate with other centers forming the Pediatric Cardiac Genomics Consortium in order to accelerate clinical protocols investigating the genetic causes and contributions to congenital heart disease (CHD). Our proposed center will be a mini-consortium, drawing potential subjects from two moderate-sized New York city metropolitan area CHD programs, each overseen locally by pediatric cardiologists who will work with research coordinators, and will leverage existing infrastructure for CHD patient recruitment from a previous NHLBI-funded SCCOR program. The proposed clinical protocol for this center will focus on the genetics of secundum atrial septal defects (2? ASDs). 2? ASDs constitute roughly 10% of CHD and can occur in syndromic and non-syndromic forms;several causative genes are known.
SPECIFIC AIM 1 will test the hypotheses that large copy number variants (CNVs) cause 2? ASDs with extra-cardiac abnormalities and that rare small de novo CNVs cause isolated 2? ASDs. Array comparative genomic hybridization (aCGH) will be used to detect CNVs and comparative quantitative PCR used to confirm them.
In SPECIFIC AIM 2, we hypothesize that genes implicated in the pathogenesis of 2? ASDs through rare large-scale genomic events are more commonly mutated through single-base pair substitutions. To test this, we will focus on candidate genes identified by novel de novo loss CNVs from the studies for SPECIFIC AIM 1. Further, we hypothesize that as-yet-unknown 2? ASD genes encode proteins that are functionally networked with those encoded by genes already identified as causing 2? ASDs when mutated. We will explore that using a systems biology approach, seeding with currently known 2? ASD genes, to generate protein interaction networks. Candidate gene lists from both approaches will be tested using resequencing of coding exons In 2? ASD subjects and controls.
In SPECIFIC AIM 3, we hypothesize that somatically acquired point mutations in 2? ASD genes contribute to the pathogenesis of those defects. To test this idea, we will use matched genomic DNA samples extracted from peripheral blood leucocytes and atrial septum primum biopsies from subjects with 2? ASDs and resequence the set of currently known 2? ASD genes. We will also resequence a comparable number of unrelated genes in order to determine the background rate of somatic mosaicism. Taken as a whole, we are leveraging advances in genomics technology to delineate the range of gene mutations and genetic mechanisms that lead to 2? ASD. Successfully completed, the findings will be important for clinical care and clinical trials, and may provide insights into how to find genetic causes for other forms of CHD.

Public Health Relevance

Congenital heart defects are the commonest form of birth defects and, despite substantial progress in care, continue to result in significant illness and premature death. For most heart defects, the cause is unknown but genetics is believed to be a critical one. Here, we will participate in a research network devoted to uncovering genetic causes of cardiovascular disease in children and specifically propose to study abnormal openings between the upper chambers of the heart, known as atrial septal defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL098123-05
Application #
8502314
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S2))
Program Officer
Kaltman, Jonathan R
Project Start
2009-09-30
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$744,670
Indirect Cost
$265,965
Name
Icahn School of Medicine at Mount Sinai
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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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
Gelb, Bruce D; Chung, Wendy K (2014) Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb Perspect Med 4:a013953
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
Subramanian, Sailakshmi; Di Pierro, Valentina; Shah, Hardik et al. (2013) MiST: a new approach to variant detection in deep sequencing datasets. Nucleic Acids Res 41:e154