CMR-based phenotyping guides genotype interpretation in hypertrophic cardiomyopathy: insights from MYH7, MYBPC3, and variants of uncertain significance

Background The phenotypic distinction between MYH7 and MYBPC3, the two major causative genes of hypertrophic cardiomyopathy (HCM), remains unclear, limiting genotype-informed management. In addition, the clinical interpretation of variants of uncertain significance (VUS) poses a persistent challenge. Objectives This study aims to delineate genotype-specific myocardial phenotypes using advanced cardiac magnetic resonance (CMR) and to evaluate the potential of CMR in clarifying the significance of VUS. Methods From a cohort of 15,768 cases, we enrolled HCM patients carrying MYH7/MYBPC3 variants (P/LP or VUS) as well as genotype-negative HCM controls. All patients underwent multiparametric CMR analysis including late gadolinium enhancement (LGE), strain analysis, and pressure-volume loop derivation. Multivariable regression and mediation analysis were performed. Results MYBPC3 variant carriers exhibited greater wall thickness, larger LGE mass (8.1 [2.6-19.4] vs. 4.7 [1.0-13.7], p < 0.05), and impaired global radial strain compared to MYH7 carriers. In contrast, MYH7 carriers demonstrated higher end-systolic elastance (3.1 [2.5-4.0] vs. 2.7 [2.4-3.3], p < 0.05), larger left atrial volume index, and greater left ventricular torsion. Notably, even in the absence of LVOT obstruction, MYH7 carriers showed significantly larger left atrial volume index and higher LV torsion compared to MYBPC3 carriers, highlighting the intrinsic hypercontractile phenotype associated with MYH7 mutations. Logistic regression identified LVOT obstruction, lower LV mass index, larger left atrial volume index, and higher LV torsion as independent predictors distinguishing MYH7 from MYBPC3 carriers. Mediation analysis revealed that myocardial fibrosis mediated approximately 38.96% of the relationship between wall thickness and end-systolic elastance. Conclusion CMR reveals distinct phenotypic patterns in HCM associated with MYH7 and MYBPC3 variants. MYH7 carriers exhibit higher end-systolic elastance, larger left atrial volume, and greater ventricular torsion, even without outflow obstruction, suggesting hypercontractile pathophysiology. MYBPC3 carriers demonstrate thicker walls, more fibrosis, and impaired radial strain. CMR phenotypes closely mirror pathogenic profiles in MYH7-VUS patients, supporting their potential pathogenicity, while MYBPC3-VUS shows intermediate features. These imaging insights enhance genotype-phenotype correlation and aid in variant interpretation, advancing precision management of HCM.Comparison of CMR Characteristics.