# Defining Genetic Architecture and Pathways of DCM

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $746,700

## Abstract

ABSTRACT
Heart failure (HF), a leading cause for cardiac transplantation and premature death, is usually preceded by
ventricular dilatation and diminished systolic performance or dilated cardiomyopathy (DCM). DCM has many
etiologies, including damaging variants in genes with diverse functions in cardiac biology. During the prior
funding period we showed that the most common genetic cause of DCM was truncating variants in titin
(TTNtv). These account for 25% of familial and 12% of sporadic DCM and for ~10% of DCM that occurs with
pregnancy, alcohol abuse, and after cancer therapies. In addition, ~0.2% of the general population carries a
TTNtv; these individuals have substantially higher lifelong risks for developing DCM and heart failure. We also
identified mechanisms by which TTNtv and other recently recognized DCM genes (FLNC and ALPK3) cause
disease. With this competitive renewal we propose to focus on the discovery of genes and mechanisms that
account for unexplained DCM, which remains an unmet need.
 We propose that some unexplained DCM is mechanistically related to established genetic causes and
results from sequence variants that are not routinely interrogated, or that have unclear functional
consequences. We will study the roles of somatic variants, non-coding regulatory variants, mitochondrial
variants, and variants of unknown significance (VUS) in established and newly identified DCM genes. We will
also define cell populations and transcriptional profiles of all cells in human hearts with unexplained DCM and
DCM with established genetic etiologies, so as to identify shared or distinct pathways that may inform
therapeutic opportunities.
 Our analyses will employ state-of-the art technologies. We will exploit whole genome sequencing
(WGS) from blood- and cardiac tissue-derived DNAs obtained from unexplained DCM subjects. We will use
single nuclear RNA sequencing (NucSeq) to define how cell populations and transcription change in DCM
hearts in comparison to normal hearts, using our recently completed normal human heart NucSeq data. We
will perturb new identified variants and mechanisms in iPSC-CMs and mouse models.
 These studies will improve knowledge of the molecules and pathways that enable normal heart
function, the molecular causes and mechanisms of DCM, information that will improve diagnosis and inform
precision therapies to prevent heart failure. Our analyses will also contribute functional insights into noncoding
sequences. To accomplish these goals, we will: 1) Identify coding and non-coding, germline and somatic
variants that contribute to unexplained DCM; 2) Define perturbed cell populations and associated
transcriptional profiles in hearts from variant-positive and unexplained DCM; 3) Define DCM
mechanisms using engineered iPSC-CMs and mouse models.

## Key facts

- **NIH application ID:** 10121732
- **Project number:** 2R01HL080494-13
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** CHRISTOPHER S CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $746,700
- **Award type:** 2
- **Project period:** 2005-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121732

## Citation

> US National Institutes of Health, RePORTER application 10121732, Defining Genetic Architecture and Pathways of DCM (2R01HL080494-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10121732. Licensed CC0.

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