A seminal discovery deriving from the Human Genome Project is that our genomes harbor a substantial number of deletions and duplications. With the technical means to find them, we now know that large de novo copy number variations (CNVs) underlie a wide range of human disease including congenital heart defects (CHD). Pathologic CNVs are particularly prevalent among individuals with CHD plus mental retardation or other organ involvement. To date, studies of CNVs in CHD have focused on characterizing their types in selected patients or on using these genomic events to drive gene discovery. Here, the PI intends to study the biomarker of rare CNVs >500 kb in two cohorts of infants with CHD with single ventricle, particularly hypoplastic left heart syndrome, obtained from Pediatric Heart Network (PHN) clinical trials. The fundamental goal of this research is to determine the impact of pathologic CNVs on typical endpoints used in CHD clinical research: neurocognitive development and somatic growth. Two PHN trials, Infants with Single Ventricle (ISV) and Single Ventricle Reconstruction (SVR), enrolled newborns with single ventricle physiology and then randomized them to two treatment arms (ISV: enalapril vs. placebo;SVR: Norwood procedure vs. Norwood with Sano modification procedure). Both trials assessed survivors at 14 months of age with identical measures of somatic growth and neurocognitive development. Genomic DNAs were amassed prospectively for ISV and are being collected for the SVR Extension.
In SPECIFIC AIM 1, we will test the hypothesis that pathologic CNVs >500 kb are prevalent among infants with single ventricle defects (expected frequency of 15%) and that those subjects who are positive for this biomarker will be skewed with respect to specific cardiac diagnosis. We will scan genomic DNAs with array comparative genomic hybridization (aCGH), confirm potential pathogenic CNVs and then dichotomize subjects as positive for this pathologic CNVs (genotype+) or negative for them (genotype-). Then, we will assess the frequency of pathologic large CNVs, compare entry characteristics of sex, race/ethnicity, birth weight, cardiac diagnoses in the genotype+ and - groups. We will also examine specific CNVs to determine the prevalence of specific genetic diagnoses (e.g., Turner syndrome), known karyotypic abnormalities associated with CHD, and recurrent chromosome aberrations potentially defining new syndromes.
In SPECIFIC AIM 2, we hypothesize that the neurocognitive and somatic growth outcomes of the genotype+ subgroup will be inferior to the genotype- subgroup. To test these, we will compare the genotype+ and - subgroups with respect to neurocognitive outcomes at 14 months of age as measured with the Bayley Scales of Infant Development-II instrument as well as the somatic growth endpoints of weight-, height-, and head circumference-for-age Z-scores at that same time point. We will also assess the impact of genotype on the results of the ISV and SVR trials (neither trial outcome has been released). That is, we will determine if the presence of the genotype+ subjects confounded trial outcomes. Taken as a whole, we are leveraging advances in genomic technologies to delineate a biomarker for genetic mechanisms leading to complex CHD. Successfully completed, the findings will be important for clinical care and clinical trials of children with single ventricle heart defects and likely CHD more broadly.

Public Health Relevance

This project seeks to establish large genomic events (deletions and duplications) as a biomarker that is determinative factor for neurocognitive and somatic growth outcomes in children with particular forms of congenital heart disease. If successful, use of genomic scanning will become standard of care for infants with such heart disease and essential for future clinical trials.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Pearson, Gail D
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Carey, Abigail S; Liang, Li; Edwards, Jonathan et al. (2013) Effect of copy number variants on outcomes for infants with single ventricle heart defects. Circ Cardiovasc Genet 6:444-51