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Elucidating the contributions of genetic variation to congenital heart disease causality and outcomes

Award Number: P01HL187164
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Elucidating the contributions of genetic variation to congenital heart disease causality and outcomes - Overall - Project Summary Congenital heart defects (CHD) are the commonest class of birth defects and the leading cause of birth defect- related infant mortality. CHD survivors face long-term disabilities and heightened risk of premature mortality. Robust epidemiologic evidence has shown that CHD is principally genetic in etiology. Over the past 16 years, the Pediatric Cardiac Genomics Consortium (PCGC) assembled a large CHD DNA and cardiac tissue biobank and generated extensive genomic data integrated with health records and imaging. Despite advances in our understanding of CHD genetics, the goal of completely understanding genetic variation’s roles in CHD causality and outcomes remains unmet. Through this program project grant (PPG), our investigators will advance our understanding of genetic causes of CHD and the interplay of genetic variation with other factors in determining CHD outcomes. Our PPG is structured around four synergistic projects supported by administrative and computational cores. The overall specific aims are: Aim 1) To deepen our understanding of the genetic causality of CHD. Half of CHD causality is currently unknown. In Project 1, we will expand the understanding of CHD causality using novel analytics of existing sequencing data, long-read sequencing to assess structural variation and DNA methylation, and increased power relying on clinical sequencing data. Discoveries from Project 1 will inform Projects 2 and 4 by supplying novel candidate genes and variants and will interact with Project 3, which will use single-cell and spatial transcriptomics for CHD tissues to prioritize genes and reveal mechanistic insights. Aim 2) To uncover drivers of variability in cardiac and non-cardiac outcomes among individuals with CHD. Projects 2 and 4 will harness multi-modal datasets, the former relying on genomic and outcomes data from the PCGC and the latter relying on one from a single clinical site that includes serial brain imaging of CHD survivors, applying cutting-edge machine learning and AI methodologies to generate predictive models for long-term outcomes. These efforts will interact with Project 1, which will identify causal variants driving those outcomes, and Project 3, which will offer mechanistic insights into pathways shaping cardiac functional outcomes. Aim 3) To gain mechanistic insights into the roles of genetic variation in altering cell composition and gene expression in CHD cardiac tissues. A powerful asset for understanding CHD is access to discarded cardiac tissues. In Project 3, we will employ spatial and single- nuclear transcriptomics to elucidate developmental perturbations in cardiac cell types and gene expression, focusing on tetralogy of Fallot and hypoplastic left heart syndrome. Insights from these studies will guide the discovery of causal genetic variation (Project 1) and help explain variability in cardiac outcomes of these critical forms of CHD (Project 2). In summary, this PPG will transform our understanding of how diverse forms of genetic variation cause CHD and impact outcomes in CHD survivors. These discoveries will improve clinical care and enable novel therapeutic approaches to reduce CHD co-morbidities.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $3,095,910 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	1	8/20/2026	NEW	$3,095,910
														Subtotal = $3,095,910

Grand Total All Awards = $3,095,910

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Elucidating the contributions of genetic variation to congenital heart disease causality and outcomes

Award Number: P01HL187164

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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