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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Impact: We analyzed the genetic causes and genotype-phenotype correlations in 68 children diagnosed with HCM during the first year of life. Patients with sarcomeric mutations demonstrated a more favorable prognosis, whereas metabolic gene-related HCM cases were the highest one- and five-year mortality rates due to HF. We identified several factors associated with unfavorable outcomes, including LV thickness, HF class, elevated troponin, increased NT-proBNP levels, and RV hypertrophy. We proposed several new and previously unreported genes, such as ROBO4 and KMT2D, as potentially causative for infantile HCM. The true role of these genes in this disease requires confirmation.