The clinical and genetic spectrum of pediatric hypertrophic cardiomyopathy manifesting before one year of age

Abstract

Hypertrophic cardiomyopathy (HCM) presents a wide range of clinical scenarios depending on the age of manifestation, with a less favorable prognosis in children. The genetic spectrum and clinical causes of HCM diagnosed before one year of age is rarely reported. We analyzed the genetic causes and genotype-phenotype correlations in 68 children diagnosed with HCM during the first year of life. Genetic analysis was performed using targeted gene sequencing (39 HCM-related genes), followed by whole-exome sequencing for genotype-negative cases. The genetic data were correlated with clinical characteristics, disease progression, and prognosis. The overall genotype-positive rate was 81%, with an equal proportion of sarcomeric (29%) and RAS-related genetic cases (29%). Gestational diabetes in mothers was more frequently observed in children with variants in Z-disc-related genes. Overall, one year-survival rate from all causes was 91.2%, with the best survival outcomes associated with sarcomeric and Z-disk-related gene variants. HCM manifesting in children before one year of age showed an approximately equal proportion of sarcomeric and RAS cascade-related cases. A more favorable prognosis was associated with sarcomeric mutations; whereas metabolic gene-related HCM cases were characterized by the highest one-and five-year mortality due to heart failure.