Cumulative Genetic Burden Defines a Gradient of Risk in MYBPC3 -Related Hypertrophic Cardiomyopathy

BACKGROUND: MYBPC3 truncating variants ( MYBPC3tv ) represent the most common genetic substrate in hypertrophic cardiomyopathy, yet carriers show substantial phenotypic variability despite a shared mechanism of haploinsufficiency. The contribution of additional genetic variants to this variability remains incompletely defined. METHODS: We analyzed 11 991 unrelated hypertrophic cardiomyopathy probands undergoing clinical genetic testing. Analyses focused on MYBPC3tv carriers stratified by additional intermediate-effect variants (IEVs) or second monogenic variants. IEVs were further classified as sarcomeric or nonsarcomeric. All probands were genetically characterized at a single center using standardized sequencing protocols, with uniform ascertainment of IEVs throughout the study period. Primary outcomes included age-related penetrance, maximal left ventricular wall thickness, and major adverse cardiovascular events; independent predictors were assessed by a multivariable Cox regression model. RESULTS: Among 2767 genotype-positive probands, MYBPC3 accounted for 47.6% of cases, with truncating variants representing 81.9% of MYBPC3 -positive individuals. Within MYBPC3tv carriers, additional variants were associated with a stepwise gradient of disease severity. Median age at diagnosis decreased from 48 years in isolated carriers to 42 years in MYBPC3tv +IEV and 28 years in double-monogenic carriers, whereas mean wall thickness increased from 21.3 to 24.1 and 26.3 mm, respectively. In multivariable analyses, cumulative genetic burden remained an independent predictor of major adverse cardiovascular event. Sarcomeric IEV carriers (hazard ratio, 10.3 [95% CI, 2.3–28.7]) and biallelic MYBPC3 carriers (hazard ratio, 23.2 [95% CI, 5.3–115.0]) exhibited the highest risk, although estimates in these subgroups should be interpreted cautiously given the limited number of events. All biallelic MYBPC3 carriers were diagnosed in childhood. CONCLUSIONS: Cumulative rare variant burden explains a subset of the phenotypic heterogeneity among MYBPC3tv carriers, defining a hierarchical gradient of disease expression. Intermediate-effect alleles and second monogenic variants, particularly biallelic MYBPC3 , identify higher-risk subgroups that may benefit from intensified surveillance, individualized management, and guided therapies.