# Oligogenic Models of Cardiomyopathy

> **NIH NIH R01** · RADY PEDIATRIC GENOMICS & SYSTEMS MEDICINE INSTITUTE · 2021 · $769,729

## Abstract

Project Summary
Background: Cardiomyopathy (CM) is a devastating disease that affects millions in the USA. Like many
autosomal dominant diseases CM has highly variable penetrance and expressivity. One genetic mechanism
that could account for this is epistasis, wherein multiple variants in the same or different genes act together to
modify phenotypes. Interestingly, epistatic variants need not be pathogenic on their own, but may only act to
modify existing pathogenic variants in the genome. A corollary to this is that epistatic variants need not be rare
or as deleterious to gene function as pathogenic variants. In the past 5 years there have been numerous,
independent reports of digenic inheritance in clinical CM cohorts. There have also been a small handful of
reports of epistasis in mouse models of CM. However, there are few, if any, published reports testing clinically
identified epistatic inheritance in a model system to establish causality, a critical unmet need. Hypothesis:
Multiple pathogenic mutations lead to more severe phenotype in CM and seemingly benign variants cause
more severe disease in combination with known pathogenic variants. Specific Aims: Aim1: Identify candidate
epistatic interactors for CM. Aim 2: Functionally test combinations of known, seemingly benign and pathogenic
variants. Study design: Aim1: We will use an existing algorithm which prioritizes variants for pathogenicity in
CM and modify it to permit discovery of epistatic variants in large publicly available cohorts of CM patients and
normal populations. We will also sequence and analyze 40 additional patients with CM followed at Rady
Children's Hospital. Aim 2: Combinations of pathogenic mutations in TTN, MYH7, LDB3 and MYBPC3, known
CM genes, will be functionally tested in human induced pluripotent stem cell derived cardiomyocytes. Mutation-
induced biochemical structural and functional phenotypes will be examined, representing a range of cardiac
phenotypes. Likewise, we will test a specific, seemingly benign mutation in MYBPC3 (p.R326Q) – a variant
enriched in an existing CM cohort and correlated with increased clinical severity – in the genetic background of
known pathogenic mutations in LDB3 and MYBPC3. We will also test the 6 best candidates from Aim 1 in
pathogenic backgrounds. The best candidates from the in vitro model will be assessed in a mouse model.
Assessment will be performed in the basal state and after cardiac stress via ventricular pressure overload.
Clinical Significance: Currently, genetic diagnoses of CM often fail to predict severity or incidence of heart
failure, significantly increasing likelihood of death in CM patients. This is driven in part by poor understanding
of genetic interactions in CM. This work will alter how some uncommon variants are interpreted in a clinical
setting, improving ability to predict phenotype. Further, this work will provide critically needed data to help
generate computational models to predict polygenic inheritance...

## Key facts

- **NIH application ID:** 10218264
- **Project number:** 5R01HL145175-03
- **Recipient organization:** RADY PEDIATRIC GENOMICS & SYSTEMS MEDICINE INSTITUTE
- **Principal Investigator:** Matthew Neil Bainbridge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $769,729
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218264

## Citation

> US National Institutes of Health, RePORTER application 10218264, Oligogenic Models of Cardiomyopathy (5R01HL145175-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218264. Licensed CC0.

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