Related Experiment Video

Updated: Sep 17, 2025

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

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Polygenic Background and Penetrance of Pathogenic Variants in Hypertrophic and Dilated Cardiomyopathies

Sarah A Abramowitz1,2, Lily Hoffman-Andrews3, David Zhang4,5

  • 1Department of Surgery, University of Pennsylvania Perelman School of Medicine.

Medrxiv : the Preprint Server for Health Sciences
|June 30, 2025
PubMed

Insights

Polygenic background significantly influences risk for hypertrophic (HCM) and dilated (DCM) cardiomyopathies, affecting disease development and offering new predictive insights. Understanding this interplay is crucial for managing these inherited heart conditions.

Area of Science:

  • Cardiovascular Genetics
  • Genomics
  • Precision Medicine

Background:

  • Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are distinct heart muscle diseases with complex genetic underpinnings.
  • Polygenic background is known to modify disease risk, but its bidirectional interaction with monogenic risk in HCM and DCM is not well understood.

Purpose of the Study:

  • To investigate how polygenic background influences the pathogenicity of rare variants associated with HCM and DCM.
  • To determine if polygenic susceptibility for one cardiomyopathy type confers protection against the other.

Main Methods:

  • A cross-sectional study utilizing data from the Penn Medicine BioBank (PMBB).
  • Analysis of 49,434 participants with available electronic health record and genotyping data.
  • Calculation of normalized polygenic scores (PGS) for HCM and DCM, alongside carrier status for known pathogenic variants.

Main Results:

  • Increased HCM PGS correlated with features of HCM (e.g., increased septal thickness) and decreased risk of DCM.
  • Increased DCM PGS correlated with features of DCM (e.g., decreased ejection fraction) and decreased risk of HCM.
  • Polygenic and monogenic risk factors had independent effects, and including PGS improved disease prediction models.

Conclusions:

  • Polygenic background significantly modifies the risk and presentation of both HCM and DCM.
  • The interplay between polygenic and monogenic factors suggests an overlapping spectrum of susceptibility.
  • Incorporating polygenic risk scores may enhance the clinical understanding and prediction of inherited cardiomyopathies.
Abstract

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