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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Genetic Spectrum, Clinical Characteristics, and Molecular Pathogenesis of Hypertrophic Cardiomyopathy Requiring Heart

Sofiya Andreeva1, Lyubov Korneva1, Mariya Marusova1

  • 1Almazov National Medical Research Center, 197341 Saint-Petersburg, Russia.

Journal of Cardiovascular Development and Disease
|December 24, 2025
PubMed

Insights

Genetic variants in hypertrophic cardiomyopathy (HCM) leading to heart failure and heart transplantation (HT) are common. Non-sarcomeric genes and Danon disease are more frequent in this severe HCM subgroup.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Epidemiology

Background:

  • Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and subsequent heart transplantation (HT) represents a rare but severe clinical outcome.
  • The genetic underpinnings and molecular pathogenesis of this specific HCM subgroup remain incompletely understood.

Purpose of the Study:

  • To investigate the genetic spectrum and molecular pathogenesis of patients with HCM who progress to end-stage heart failure and require HT.
  • To characterize the genetic variants associated with adverse cardiac remodeling (dilated/hypokinetic and restrictive phenotypes) in this patient cohort.

Main Methods:

  • Retrospective cohort study of 14 patients with HCM undergoing HT.
  • Genetic analysis to identify pathogenic or likely pathogenic variants.
  • Functional studies including electrophoretic analysis of titin in myocardial samples for select cases.

Main Results:

  • A high prevalence (93%) of pathogenic/likely pathogenic genetic variants was identified in the studied cohort.
  • Dilated/hypokinetic remodeling was linked to loss-of-function variants in non-sarcomeric genes like *LAMP2* (especially in females), and sarcomeric genes (*MYH7*, *MYBPC3*, *FLNC*, *TTN*).
  • Restrictive phenotype was associated with multiple sarcomeric gene variants (*MYL3*, *MYBPC3*+*TPM1*, *MYH7*, *TNNT2*).

Conclusions:

  • HCM progressing to HT exhibits a higher frequency of variants in non-sarcomeric genes and a notable association with Danon disease compared to the general HCM population.
  • Specific genetic variants, including those in *LAMP2*, are associated with dilated remodeling in this severe HCM subset.
  • The findings highlight the complex genetic architecture contributing to the progression of HCM to end-stage heart failure and the need for heart transplantation.

Keywords:
Danon diseaseadverse remodelingdilated phenotypefilamin Cheart transplantationhypertrophic cardiomyopathynon-sarcomeric genetic variantsrestrictive phenotypetitintruncating variants

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