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Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance

Award Number: R01HL160863
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance - PROJECT SUMMARY/ABSTRACT Sequencing an individual’s genome now costs less than many routine medical procedures. A resulting vision is that everyone will have their genome sequenced early in life to enable individualized medical advice about disease prevention and drug selection. A major concern with this vision, however, is proper interpretation of the overwhelming volume of discovered novel and rare variants. In other contexts, a new diagnostic test can be benchmarked and validated in studies that compare large populations with and without a disorder to determine the predictive value of a positive result. In the genetic sequencing context, however, a positive test for most variants cannot be applied to enough heterozygous individuals for a definitive association with disease. Pathogenic variants in KCNH2 (a.k.a. hERG, a cardiac potassium channel gene critical for cardiomyocyte repolarization) can cause sudden cardiac death in the young and can predispose carriers to drug-induced arrhythmias. Genetic variants in KCNH2 are responsible for ~ 6% of autopsy-negative sudden unexplained death in the young and ~ 1% of sudden infant death syndrome cases. Additionally, among heterozygous carriers of variants in KCNH2, women are at greater overall risk of a severe event (including sudden cardiac death) which is increased in the postpartum period. Since most disease-associated variants in KCNH2 are rare, full exome sequencing has the potential to identify those individuals at greater risk early in life before any phenotype manifests. However, even among heterozygous carriers of KCNH2 variants definitively associated with disease, not all develop the same phenotype. To address the challenge of variant interpretation, the American College of Medical Genetics and Genomics suggests criteria to incorporate variant population, functional, computational, and segregation data using several described heuristics. Our foundational hypothesis is that clinically meaningful knowledge is lost in the compression of these variant-specific data to a dichotomous classification. To investigate this hypothesis, we will generate in vitro data for all missense variants in KCNH2 prospectively, build a prediction model of disease penetrance, and validate resulting predictions against the incidence of arrhythmias and cardiac events for variants observed in the Electronic Medical Records and Genomics Network (eMERGE), a Leducq Transatlantic Network, and the UK Biobank.


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 = $565,681 )
2026	2026	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	5	5/1/2026	NON-COMPETING CONTINUATION	$17,317
2026	2026	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	5	3/20/2026	NON-COMPETING CONTINUATION	$548,364
														Subtotal = $565,681

Issue Date FY: 2025 ( Subtotal = $577,225 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	12/31/2024	NON-COMPETING CONTINUATION	$519,502
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	4	8/14/2025	NON-COMPETING CONTINUATION	$57,723
														Subtotal = $577,225

Issue Date FY: 2024 ( Subtotal = $584,720 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	1/11/2024	NON-COMPETING CONTINUATION	$536,988
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$47,732
														Subtotal = $584,720

Issue Date FY: 2023 ( Subtotal = $596,653 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	2/1/2023	NON-COMPETING CONTINUATION	$596,653
														Subtotal = $596,653

Issue Date FY: 2022 ( Subtotal = $596,653 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	1/27/2022	NEW	$596,653
														Subtotal = $596,653

Grand Total All Awards = $2,920,932

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Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance

Award Number: R01HL160863

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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