Carrying two pathogenic/likely pathogenic variants increased the risk of major cardiac events in pediatric hypertrophic cardiomyopathy compared to a single variant (HR 8; 95% CI 5.6-10.4; p<0.001).
Cohort (n=53)
No
Does the presence of multiple pathogenic genetic variants increase the risk of major cardiac events in children with early-onset hypertrophic cardiomyopathy compared to a single variant?
In pediatric early-onset hypertrophic cardiomyopathy, the presence of multiple pathogenic genetic variants strongly modifies phenotypic severity and markedly increases the risk of major cardiac events.
Hazard Ratio: 8 (95% CI 5.6–10.4)
p-value: p=<0.001
Abstract Background Paediatric-onset hypertrophic cardiomyopathy (HCM) is rare but associated with high mortality rates. While most cases are attributed to single pathogenic variants in sarcomeric genes, the contribution of multiple genetic variants to early disease expression and adverse outcomes in children remains insufficiently characterized. We aimed to define the molecular architecture of early-onset HCM and assess the impact of multiple genetic variants on clinical severity. Methods We conducted a single-centre retrospective study of all paediatric patients (≤18 years) evaluated between 2014 and 2024 for early-onset HCM. All individuals underwent comprehensive genetic testing using next-generation sequencing panels targeting 116 cardiomyopathy-associated genes. Genetic findings were classified following ACMG/AMP criteria. Cardiac events (CEs) included sustained ventricular tachycardia/fibrillation, appropriate ICD therapies, sudden cardiac death or arrest, heart failure stages C–D, and heart transplantation. Cox proportional hazards models assessed the association between variant burden and CEs. Results Of 202 children evaluated for cardiomyopathy, 53 were diagnosed with HCM (median age 12 years; IQR 2–14). A definitive genetic diagnosis was established in 62% of cases. Paediatric HCM patients carrying multiple rare variants exhibited a markedly increased CE risk. The highest risk was observed in carriers of two pathogenic/likely pathogenic (P/LP) variants (HR 8; p0.001; 95% CI 5.6;10.4). In contrast, children with a single P/LP variant demonstrated substantially lower event rates. Conclusions Early-onset HCM is frequently monogenic; however, multiple deleterious variant burden strongly modifies phenotypic severity and markedly increases the risk of major cardiac events in childhood. These findings underscore the need for systematic, comprehensive genetic testing in paediatric HCM to identify high-risk genotypes that may inform prognosis and tailored management.
Barrios et al. (Mon,) conducted a cohort in Early-onset hypertrophic cardiomyopathy (n=53). Two pathogenic/likely pathogenic (P/LP) variants vs. Single P/LP variant was evaluated on Cardiac events (sustained ventricular tachycardia/fibrillation, appropriate ICD therapies, sudden cardiac death or arrest, heart failure stages C–D, and heart transplantation) (HR 8, 95% CI 5.6-10.4, p=<0.001). Carrying two pathogenic/likely pathogenic variants increased the risk of major cardiac events in pediatric hypertrophic cardiomyopathy compared to a single variant (HR 8; 95% CI 5.6-10.4; p<0.001).