Genomic Architecture and Cascade Screening Gaps in Hypertrophic Cardiomyopathy: A Real-World Analysis

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is genetically heterogeneous, involving more than 11 genes. Since HCM genetic testing was covered by Japan’s national health insurance in 2022, variant detection and the need for family-based intervention have increased, although funding is limited to symptomatic patients only. In this study, we evaluated institutional genetic testing outcomes, factors associated with pathogenic variants, and follow-up of at-risk relatives. Methods: We retrospectively analyzed individuals with confirmed or suspected HCM who underwent genetic testing between October 2022 and June 2025. Data regarding molecular results, family history of cardiomyopathy or sudden cardiac death in first-, second-, and third-degree relatives, and cascade screening were collected. Statistical analysis was performed using R version 2025.09.2 + 418. Results: Among 33 probands (median age, 54 years; 51% male), 13 individuals (39%) had pathogenic or likely pathogenic variants (PV or LPV), while six (18%) harbored variants of uncertain significance (VUS), and 14 (43%) yielded negative results. The PV or LPV cohort was significantly younger at the time of testing (median, 34 vs. 59 years; p = 0.008) and had a family history of PV or LPV (77% vs. 20%; p = 0.005). Only three relatives from two PV or LPV probands underwent cascade genetic screening; two tested positive and initiated targeted cardiac surveillance. Conclusions: Despite achieving actionable results, the restricted uptake of cascade screening highlights the need for improved communication and systemic support to facilitate family-based testing and precision medicine.