# Cis regulatory variants of haploinsufficiency genes as cardiomyopathy modifiers

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $756,039

## Abstract

Abstract:
Cardiomyopathies, occurring in ~1:250 in the population, are disorders with primary impairment of heart muscle
structure and function. Approximately 40-50% of the major cardiomyopathy subtypes can be explained as
autosomal dominant with incomplete penetrance. Variants causing large subsets of cardiomyopathy are present
in genes wherein truncating variants (TVs) are the most common variant class. In particular, MYBPC3TV are the
most common cause of hypertrophic cardiomyopathy (HCM), and DSPTV are the most common cause of
arrhythmogenic left ventricular cardiomyopathy (ALVC). In prior work and preliminary data, we have clearly
shown loss of function to be the primary mechanism for both MYBPC3TV and DSPTV – thus, MYBPC3TV and
DSPTV can be considered prototypical causes of haploinsufficiency-associated cardiomyopathy. However,
despite knowledge of the genetic mechanisms for these conditions, precision medicine approaches are hindered
by the fact that marked variability in clinical severity occurs among patients of all genetic subtypes, likely in large
part due to genetic modifiers. Given the strong evidence of haploinsufficiency, noncoding variants that influence
the effective “dose” of the causal genes are highly likely to contribute to expressivity of cardiomyopathy for genes
such as MYBPC3 and DSP. We show that single nucleotide variants (SNVs) in cis regulatory elements (CREs)
of these genes are common in the population, and are associated with allelic imbalance. In addition to these
potential cis modifiers, recent genome wide association studies (GWASs) have discovered putative modifiers in
protein quality control pathways that could affect gene dose downstream of transcription, but the causative SNVs
and their potential additive effects have not been determined. This proposal will test the central hypothesis that
variation in CREs strongly impacts the severity of haploinsufficiency-associated cardiomyopathy by altering the
effective gene dose. In Aim 1, we will quantify gene-expression effects of all possible SNVs in the major CREs
of MYBPC3 and DSP. Using human induced pluripotent stem cell cardiomyocytes (iPSC-CMs), we will perform
massively parallel reporter assays (MPRAs) with synthetic saturation mutagenesis of these CREs. We will also
determine causal SNVs in linkage disequilibrium with variants found on prior GWAS’s through MPRAs. We will
test for additive effects with whole genome sequencing (WGS) and phenotypic data for patients with MYBPC3TV.
In Aim 2, we will test whether noncoding variants that disrupt highly conserved transcription factor binding sites
within the major CREs of each of MYBPC3 and DSP further reduce mRNA expression and exacerbate disease
when superimposed on MYBPC3TV and DSPTV iPSC-CM and mouse models. Taken together, this proposal will
generate noncoding regulatory maps covering >30,000 SNVs in the sequence space most likely to influence
gene expression of two major prototypes of haploinsufficiency-associa...

## Key facts

- **NIH application ID:** 10976522
- **Project number:** 1R01HL171074-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ADAM S HELMS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $756,039
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10976522

## Citation

> US National Institutes of Health, RePORTER application 10976522, Cis regulatory variants of haploinsufficiency genes as cardiomyopathy modifiers (1R01HL171074-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10976522. Licensed CC0.

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