# Leveraging Large-Scale Biobanks to Discover and Define Rare Variant Effects in Hypertrophic Cardiomyopathy

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $767,579

## Abstract

SUMMARY
Hypertrophic cardiomyopathy (HCM) affects up to 1:200 individuals and is a common cause of sudden cardiac
death. Guidelines recommend genetic testing in HCM probands to help establish diagnosis, inform risk
stratification, and identify at-risk relatives. However, causal variants are identified in fewer than half of patients,
many tests return variants of uncertain significance (VUS), and genotype-phenotype associations of known
genes are insufficiently characterized to inform medical management. In this proposal we address 4 gaps in
HCM research: 1) Most data are from individuals of European ancestry referred for genetic testing, creating bias
in estimates of the contribution, penetrance, and phenotype in the broader clinical and community population. 2)
Established HCM genes have insufficient genotype-phenotype data to inform gene-specific clinical management.
3) The evidence for most candidate genes is equivocal due to lack of study in cohorts sufficiently large to evaluate
pathogenicity. 4) Some disease loci likely remain undiscovered because GWAS and linkage approaches used
in prior studies are not well-powered for diseases, such as HCM, with variable age of onset, both high genetic
and allelic heterogeneity, and incomplete penetrance. We will address these fundamental knowledge gaps using
innovative genetic methods and a novel, large-scale HCM research platform that includes harmonized
phenotypic, genotyping, sequencing, and identity-by-descent (IBD) data from six large biobanks comprising
~1.5M participants and >5,000 HCM cases. Specifically, we propose to use rare variant and IBD-based methods
to: Aim 1) Define the contribution and phenotypic manifestations of established disease genes in multiple diverse,
non-referral HCM populations; Aim 2) Assess the pathogenicity of candidate HCM genes with equivocal evidence
and establish a novel platform to evaluate VUS in established genes; and Aim 3) Discover novel HCM loci via
IBD mapping and rare variant association within and across biobanks at scale. To balance the innovation of
these aims, we present compelling preliminary data demonstrating the feasibility of our approaches which
identified a cluster of distantly related individuals harboring a common pathogenic variant in a Mendelian
cardiomyopathy gene. We anticipate these analyses will substantially expand our understanding of the genetic
factors underlying HCM risk and their clinical manifestations. Once established, our platform will support future
clinical and genetic research and advance the long-term goal of implementing targeted interventions at the clinic
and population level to reduce the burden of HCM for all patients.

## Key facts

- **NIH application ID:** 10999711
- **Project number:** 1R01HL174052-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jennifer Below
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $767,579
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999711

## Citation

> US National Institutes of Health, RePORTER application 10999711, Leveraging Large-Scale Biobanks to Discover and Define Rare Variant Effects in Hypertrophic Cardiomyopathy (1R01HL174052-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999711. Licensed CC0.

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