Genetic insights into hypertrophic cardiomyopathy: pathogenesis, diagnosis, and therapeutic implications

Abstract

We conducted a comprehensive literature review of sarcomeric gene studies, registry analyses, and recent cohort investigations, focusing on genetic testing outcomes and clinical prognostication. Sarcomeric mutations account for approximately 60% of familial hypertrophic cardiomyopathy (HCM) cases and exhibit variable penetrance and expressivity. Additionally, mitochondrial DNA variants and nonsarcomeric genetic modifiers contribute to the phenotypic heterogeneity observed in HCM. Genetic testing facilitates diagnosis in atypical cases, guides cascade testing in families, and supports reproductive decision-making. Long-term follow-up data from registries indicate that sarcomere-positive patients are diagnosed approximately 13 years earlier and experience nearly double the 50-year incidence of adverse cardiovascular events compared to sarcomere-negative individuals. In Korean cohorts, the mutation detection rate is reported at 43.5%, with genotype-positive status independently associated with worse outcomes. However, for certain prognostic outcomes—particularly sudden cardiac death—more robust data are needed. Emerging therapies, including myosin inhibitors and gene-editing approaches, show promise in targeting the underlying molecular mechanisms of HCM. Therefore, integrating comprehensive genetic screening—including sarcomeric, mitochondrial, and modifier genes—is essential for precise risk stratification and personalized management of HCM. Future efforts should focus on refining variant interpretation and advancing genotype-guided therapeutic strategies. © The Author(s) 2025.