# Discovery and Characterization of Rare Variant Effects in Dilated Cardiomyopathy via Large-Scale Biobank Analysis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $679,562

## Abstract

SUMMARY
Dilated cardiomyopathy (DCM) affects up to 1:250 individuals and is responsible for ~40% of cardiac transplants.
Guidelines recommend genetic testing in DCM probands to help establish diagnosis, guide medical care, inform
risk stratification, and identify at-risk relatives. However, causal variants are identified in fewer than half of
patients, ~30-40% of tests return variants of uncertain significance (VUS), and a modest number of genes have
adequate genotype-phenotype data to inform medical management. In this proposal we address 4 gaps in DCM
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)
Most established DCM 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 DCM, 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 DCM research platform that includes
harmonized phenotypic, genotyping, sequencing, and identity-by-descent (IBD) data from 5 large biobanks
comprising ~1M participants and >10,000 DCM 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 DCM populations; Aim 2) Assess the pathogenicity of candidate DCM genes with
equivocal evidence and establish a novel platform to evaluate VUS in established genes; and Aim 3: Discover
novel DCM genes 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
RBM20. We anticipate these analyses will substantially expand our understanding of the genetic factors
underlying DCM 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 DCM for all patients.

## Key facts

- **NIH application ID:** 10840427
- **Project number:** 5R01HL167509-02
- **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:** $679,562
- **Award type:** 5
- **Project period:** 2023-05-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840427

## Citation

> US National Institutes of Health, RePORTER application 10840427, Discovery and Characterization of Rare Variant Effects in Dilated Cardiomyopathy via Large-Scale Biobank Analysis (5R01HL167509-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10840427. Licensed CC0.

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