Beyond monogenic Hypertrophic cardiomyopathy: multiple variant presence drives severe early-onset phenotypes in children
E Martinez Barrios, S Cesar-Diaz, A Greco, J Cruzalegui, A Lujan, F Merchan-Pinto, N Diaz-Escute, P Cerralbo, O Campuzano, G Sarquella-BrugadaAbstract
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; p<0.001; 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.