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Updated: May 5, 2026

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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High-Risk Cardiomyopathy Genotypes and Arrhythmic Risk: LMNA, FLNC, RBM20, PLN and Desmosomal Genes in the ESC 2023

Nardi Tetaj1,2, Andrea Segreti1,2, Aurora Ferro1,2

  • 1Cardiology Unit, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 200, 00128 Roma, Italy.

Genes
|May 4, 2026
PubMed

Insights

Inherited cardiomyopathies increase risk of ventricular arrhythmias and sudden cardiac death. Genotype-specific risk stratification, guided by new ESC 2023 guidelines, improves personalized prevention strategies beyond traditional measures.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Inherited cardiomyopathies are a leading cause of ventricular arrhythmias (VA) and sudden cardiac death (SCD), often without significant systolic dysfunction.
  • Current risk stratification relies heavily on left ventricular ejection fraction (LVEF), which inadequately addresses the heterogeneity of non-ischemic cardiomyopathies.
  • Advances in cardiac genetics and imaging reveal genotypes linked to disproportionate arrhythmic risk preceding ventricular remodeling.

Purpose of the Study:

  • To review cardiomyopathy-associated genotypes with high arrhythmic risk.
  • To examine molecular mechanisms, phenotypic trajectories, and arrhythmogenic profiles of these genotypes.
  • To discuss genotype-informed strategies for implantable cardioverter-defibrillator (ICD) decision-making in SCD prevention.

Main Methods:

  • Narrative review synthesizing genetic, imaging, and clinical evidence.
  • Focus on specific high-arrhythmic-risk genotypes: LMNA, FLNC, RBM20, PLN p.Arg14del, and desmosomal genes.
  • Integration of findings with the 2023 European Society of Cardiology (ESC) Guidelines on cardiomyopathies.

Main Results:

  • Specific genotypes (e.g., LMNA, FLNC, RBM20, PLN p.Arg14del, desmosomal genes) are consistently linked to increased VA and SCD risk.
  • Genotype-specific myocardial fibrosis, conduction disease, and VA patterns influence risk.
  • The 2023 ESC Guidelines integrate etiology, substrate, and electrical phenotype for improved risk stratification.

Conclusions:

  • Genotype-informed strategies represent a paradigm shift in personalized SCD prevention for inherited cardiomyopathies.
  • Understanding genotype-specific arrhythmogenic profiles enhances ICD decision-making beyond LVEF.
  • Further research is needed to address remaining gaps in evidence and risk prediction.

Keywords:
FLNCICDLMNAPLNRBM20cardiac MRIcardiomyopathydesmoplakindesmosomal genesgenotype–phenotypelate gadolinium enhancementsudden cardiac deathventricular arrhythmias

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