Homozygous MYBPC3+ infants had 87% death or transplant by 0.53 years; compound heterozygous had 27% by 6.95 years and 31% HF hospitalization; heterozygous had 30% HF hospitalization.
Pediatric MYBPC3-associated hypertrophic cardiomyopathy carries a severe, genotype-dependent disease burden, with homozygous patients facing extremely high rates of death or transplant in infancy.
Absolute Event Rate: 0% vs 0%
Abstract Background Pathogenic loss-of-function variants in the MYBPC3 gene are the leading genetic cause of hypertrophic cardiomyopathy (HCM). Biallelic loss-of-function variants are uniformly fatal in infancy, while phenotypic manifestations for individuals who are heterozygous remain less well understood. To bridge this gap, we analyzed data from MyCLIMB, a global natural history study of pediatric patients with MYBPC3+HCM, to better understand disease progression and its relationship to genotype and ultimately guide development of emerging therapies such as gene replacement therapy. Methods MyCLIMB is designed to characterize the natural history of pediatric patients (18 years) with cardiomyopathy due to pathogenic or likely pathogenic (P/LP) MYBPC3 variants. We obtained clinical and genetic data from 27 centers across the US, Canada, Spain and UK. As of 31 January 2025, 169 retrospective and 39 prospective patients were enrolled in MyCLIMB. This study was enriched for severe MYBPC3-associated HCM pediatric patients, including biallelic. 78 asymptomatic individuals were excluded from analysis. Patients were classified by genetic inheritance (homozygous, compound heterozygous, and heterozygous). Demographics, genotype, echocardiographic measures, prevalence of and time to major cardiac-related events were compared across cohorts with standard statistical measures. Results Homozygous infants (n=30) were diagnosed at a median age of 0.3 years and 87% of them experienced death or heart transplant by a median age of 0.53 years. Compound heterozygous children (n=11) were diagnosed at a median age of 2.9 years and 27% of them experienced death or heart transplant by a median age of 6.95 years and 30.8% experienced a heart-failure related hospitalization by a median age of 3.33 years. The prevalence of Ventricular Arrhythmia composite was 29.3% in heterozygous patients vs 72.7% in compound heterozygous, while prevalence of HF composite was 14.1% vs 36.4%, respectively. Heterozygous children (n=92) were diagnosed at a median age of 5.4 years, and had a median left ventricular mass indexed to body surface area (LVMI) of 104.5 (n=40), with heart failure associated hospitalizations of 30.4% and arrythmia-related events of 6.5%. Conclusions Homozygous patients had severe disease where majority died or received a heart transplant within the first eight months of life. Compound heterozygous MYBPC3+ HCM patients experienced a significant burden of disease and high prevalence of HF-related hospitalization and death or transplant. Severely affected heterozygous children experienced significant burden of heart failure hospitalizations and arrhythmia. Our results demonstrate the presence of significant and varying disease burden of MYBPC3+ HCM in pediatric patients, confirming the importance of genetic testing, close monitoring, and suggesting that children may also benefit from targeted effective treatments, including gene therapies.
Feingold et al. (Sat,) reported a other. Homozygous MYBPC3+ infants had 87% death or transplant by 0.53 years; compound heterozygous had 27% by 6.95 years and 31% HF hospitalization; heterozygous had 30% HF hospitalization.