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

Inherited cardiomyopathies are a leading cause of ventricular arrhythmias (VA) and sudden cardiac death (SCD). Historically, clinical decisions for primary prevention—specifically the implantation of an implantable cardioverter-defibrillator (ICD)—have relied heavily on left ventricular ejection fraction (LVEF). However, this approach often fails to capture the significant biological heterogeneity of non-ischemic cardiomyopathies, where life-threatening arrhythmias can occur even with preserved systolic function.

The 2023 European Society of Cardiology (ESC) guidelines formalize a transition toward a more personalized, genotype-informed strategy. This framework moves beyond the binary LVEF-based gatekeeper model, instead emphasizing an integrated assessment of etiology (genotype), myocardial substrate (scar/fibrosis detected by cardiac MRI), and electrical expression (e.g., non-sustained ventricular tachycardia, conduction disease, and ectopy burden). This shift recognizes that for certain high-risk genotypes, the arrhythmic substrate develops early, often preceding overt ventricular remodeling or significant systolic impairment.

This review focuses on five key genotypes consistently linked to high arrhythmic risk:

• LMNA: Often presents with an electrical-first phenotype, including conduction disease and arrhythmias, before severe systolic dysfunction.
• FLNC (truncating variants): Characterized by a scar-first phenotype with extensive inferolateral or ring-like fibrosis.
• RBM20: Associated with an aggressive, rapid progression toward both heart failure and malignant arrhythmias.
• PLN (p.Arg14del): A founder mutation causing a mixed dilated/arrhythmogenic phenotype with early fibrosis.
• Desmosomal genes (e.g., DSP, PKP2): The hallmark of arrhythmogenic cardiomyopathy (ACM), where inflammation and fibro-fatty replacement drive electrical instability.