Genotypic and phenotypic characterization of critical pediatric cardiomyopathy: A 20-patient cohort study

Pediatric cardiomyopathy (PCM) is a major cause of heart failure and cardiac transplantation, representing a common pathological condition associated with high mortality risk in the pediatric intensive care unit. The genetic basis of PCM is complex, involving various pathogenic genes across different cardiomyopathy subtypes. Despite existing large cohort studies on hereditary cardiomyopathy, data on the phenotypic characteristics and genetic variations specifically in PCM patients remain limited. This study included 20 PCM patients requiring intensive care between January 2023 and January 2025. Phenotypic information was collected, and all patients underwent trio-whole exome sequencing (trio-WES), with Sanger sequencing used for variant confirmation and molecular diagnosis. Among the 20 patients, 14 (70 %) had dilated cardiomyopathy (DCM) and six (30 %) had hypertrophic cardiomyopathy (HCM). The cohort consisted of 13 females (65 %) and seven males (35 %), with a median age of onset of 8.5 months. Molecular genetic diagnoses were achieved in nine patients (45 %), identifying variants in five DCM patients and four HCM patients. DCM-associated genes identified were EYA4, RPL3L, TTN, and FLNC. HCM-associated genes were primarily MYH7, followed by GTPBP3 and GAA. Two variants of uncertain significance were found: RPL3L p.Glu108Lys and TTN p.Arg16002Gln; the remaining variants were classified as pathogenic or likely pathogenic. Structural modeling suggested the RPL3L p.Glu108Lys variant may disrupt the protein's Loop domain, potentially affecting its structural stability and functional integrity. The study concludes that DCM is the predominant subtype in severe PCM, characterized by early onset and rapid progression. Genetic testing revealed a correlation between PCM and genetic variations with high heterogeneity. These findings highlight the genotypic and phenotypic spectrum in critically ill PCM patients and underscore the importance of early trio-WES testing for patients and family member screening.