Genotype-Phenotype Correlations Identify Phenotypic Differences in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy in the NHLBI HCM Registry

Background: Previous studies of genotype-phenotype correlations in hypertrophic cardiomyopathy (HCM) have presented inconsistent conclusions, potentially reflecting small studies and non-uniform phenotyping. Objectives: We aimed to identify genotype-phenotype correlations in sarcomeric variant-positive HCM cardiac magnetic resonance (CMR) imaging and adverse outcome data in the National Heart, Lung, and Blood Institute (NHLBI) HCM Registry. Methods: Of 2750 overall patients, 915 sarcomeric variant-positive ones were subgrouped by genotype. CMR measures of left ventricular (LV) hypertrophy, fibrosis and function, and adverse events, were compared. Findings were meta-analyzed with prior studies from systematic review. Results: Patients with pathogenic variants in thick-filament genes had greater hypertrophy than those in thin-filament genes - maximal LV wall thickness (maxLVWT) (21.7 {+/-} 5.0 vs. 20.0 {+/-} 4.4mm, P<0.01) and indexed LV mass (81.9 {+/-} 26.0 vs. 71.7 {+/-} 13.3g/m2, P<0.001). Of the former, MYBPC3 carriers had greater maxLVWT than MYH7 carriers (22.2 {+/-} 5.2 vs. 20.9 {+/-} 4.5mm, P<0.01) but lower LV ejection fraction (63.1 {+/-} 8.4 vs. 65.3 {+/-} 8.4%, P<0.001). Findings remained significant after covariate adjustment and meta-analysis. 23 (~1%) patients had >1 disease-linked variants with only 3 (~0.11%) carrying >1 pathogenic variants. MYBPC3 carriers had lower risk of a multiple event composite than MYH7 carriers. Conclusions: In the largest CMR-based study to date, we identified significant phenotypic differences that characterize disease-gene subgroups and resolved prior discrepancies through systematic review and meta-analysis. However, carriage of >1 sarcomeric variants did not contribute much to variation in phenotypic severity in the general HCM population due to its rarity.