{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:02:02Z","timestamp":1789574522262,"version":"build-2803163510"},"reference-count":104,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Inherited cardiomyopathies represent a major cause of ventricular arrhythmias (VA) and sudden cardiac death (SCD), frequently occurring in the absence of advanced systolic dysfunction. Traditional strategies for the primary prevention of SCD have relied predominantly on left ventricular ejection fraction (LVEF), an approach that fails to capture the substantial biological and clinical heterogeneity of non-ischemic cardiomyopathies. Over the past decade, advances in cardiac genetics and cardiac magnetic resonance imaging have identified specific genotypes associated with a disproportionate arrhythmic risk, which often precedes overt ventricular remodeling. The 2023 European Society of Cardiology (ESC) Guidelines on cardiomyopathies formalize this paradigm shift by integrating etiology, myocardial substrate, and electrical phenotype into contemporary risk stratification. In this narrative review, we focus on cardiomyopathy-associated genotypes consistently linked to high arrhythmic risk\u2014LMNA, truncating variants in FLNC, RBM20, PLN p.Arg14del, and desmosomal genes\u2014and examine their molecular mechanisms, phenotypic trajectories, and arrhythmogenic profiles. We discuss how genotype-specific patterns of myocardial fibrosis, conduction disease, and VA inform implantable cardioverter-defibrillator (ICD) decision-making beyond LVEF-based thresholds. By synthesizing genetic, imaging, and clinical evidence in light of ESC 2023 recommendations, this review highlights the evolving role of genotype-informed strategies in the personalized prevention of SCD and underscores remaining gaps in evidence and risk prediction.<\/jats:p>","DOI":"10.3390\/genes17040370","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T12:05:49Z","timestamp":1775563549000},"page":"370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["High-Risk Cardiomyopathy Genotypes and Arrhythmic Risk: LMNA, FLNC, RBM20, PLN and Desmosomal Genes in the ESC 2023 Era"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2906-4855","authenticated-orcid":false,"given":"Nardi","family":"Tetaj","sequence":"first","affiliation":[{"name":"Cardiology Unit, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 200, 00128 Roma, Italy"},{"name":"Research Unit of Cardiovascular Science, Department of Medicine and Surgery, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 21, 00128 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2631-8642","authenticated-orcid":false,"given":"Andrea","family":"Segreti","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 200, 00128 Roma, Italy"},{"name":"Research Unit of Cardiovascular Science, Department of Medicine and Surgery, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 21, 00128 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Ferro","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 200, 00128 Roma, Italy"},{"name":"Research Unit of Cardiovascular Science, Department of Medicine and Surgery, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 21, 00128 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Ligorio","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 200, 00128 Roma, Italy"},{"name":"Research Unit of Cardiovascular Science, Department of Medicine and Surgery, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 21, 00128 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Spagnolo","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 200, 00128 Roma, Italy"},{"name":"Research Unit of Cardiovascular Science, Department of Medicine and Surgery, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 21, 00128 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Grigioni","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 200, 00128 Roma, Italy"},{"name":"Research Unit of Cardiovascular Science, Department of Medicine and Surgery, Campus Bio-Medico Hospital University, Via Alvaro del Portillo 21, 00128 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1093\/eurheartj\/ehac262","article-title":"2022 ESC Guidelines for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death","volume":"43","author":"Zeppenfeld","year":"2022","journal-title":"Eur. 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