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/m 2 , 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. Condensed Abstract Prior studies of genotype-phenotype correlations in hypertrophic cardiomyopathy have produced inconsistent findings. In the largest study to date with CMR imaging, we identified significant correlations between disease phenotypes and genotype subgroups of sarcomeric variant-positive patients from the NHLBI Hypertrophic Cardiomyopathy Registry. Patients with disease-linked MYBPC3 variants had greater hypertrophy and lower ejection fraction than those with MYH7 variants but also less incidence of clinical outcomes. Patients with multiple variants were strikingly rare (∼1% of all patients). Ultimately, we discovered phenotypic differences that characterize rare genotype subgroups and resolved prior discrepancies through systematic review and meta-analysis.