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Uncovering incomplete penetrance genes in congenital heart disease by integrative analysis of Common Fund data

Award Number: R03OD039972
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/10/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Uncovering incomplete penetrance genes in congenital heart disease by integrative analysis of Common Fund data - PROJECT SUMMARY Congenital heart disease (CHD) is the most common birth defect and a leading cause of mortality in children. Despite a well-established heritable componentto this disorder, genetic testingis often unsuccessful. Some 60% of patients fail to receive a molecular diagnosis; for patients with isolated CHD, the failure rate is closer to 90%. Without a precise diagnosis, it is difficult to provide any patient with an accurate prognosis or personalized interventions. The main reason that diagnostic testing fails is that our knowledge of the genetic underpinnings of CHD remains woefully incomplete. CHD is not only genetically heterogeneous, but also notorious for incomplete penetrance (variants that do not always cause a condition). In this proposal we aim to quantify the role of incomplete penetrance in CHD risk genes. We will source a large cohort of CHD families fromthe Gabriella Miller Kids First resource, the Undiagnosed Disease Network, Genomics England, and an internal research study and performtwo complementary analyses to rank CHD genes. First, we will apply a genetic association study of CHD probands to prioritize genes with an increased burden of rare genetic variation among CHD patients irrespective of the inheritance pattern. This will be achieved through an innovative new resource: a remote control database of 40,000 healthy, diverse controls and a method to securely select matched controls for any given case cohort. Second, we will performpedigreeanalysis of all CHD families to identify genes in which rare large-effect variants segregate with disease. Finally, we will combine the results of both strategies into a single master table of CHD genes and use the segregation patterns observed in all families to quantify the extent of incomplete penetrance. We expect our results will serve as a reference for the diagnostic initiatives in CHD and will inform clinical geneticists about the likelihood of disease causality for genes challenged by incomplete penetrance. Our results should provide a framework for integrating association and segregation analyses that could be adapted to other genetically heterogeneous conditions.


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 = $0 )
2026	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Trans-NIH Research Support	000	1	3/2/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $316,000 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Trans-NIH Research Support	000	1	6/10/2025	NEW	$316,000
														Subtotal = $316,000

Grand Total All Awards = $316,000

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Uncovering incomplete penetrance genes in congenital heart disease by integrative analysis of Common Fund data

Award Number: R03OD039972

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/10/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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