Molecular Findings, Clinical Severity, and Transplant-Free Survival in Pediatric Cardiomyopathy: A Prospective Indian Cohort

Abstract Background The relationship between molecular findings, clinical disease severity, and heart failure (HF) outcomes in pediatric cardiomyopathy remains uncertain. Objectives To evaluate genetic diagnostic yield and the relative associations of clinical severity, biomarkers, and multimodality imaging with death or heart transplantation in children with cardiomyopathy. Methods This prospective single-center study included 235 children younger than 18 years at a South Indian referral center. Genetic testing, HF functional class, biomarkers, echocardiography, cardiac magnetic resonance (CMR), and longitudinal outcomes were evaluated. Transplant-free survival was assessed using Kaplan–Meier analysis and Cox regression. Hierarchical models evaluated incremental prognostic discrimination using Harrell's C-index. Results Genetic testing was performed in 112 children (47.7%), of whom 54 (48.2%) had reported pathogenic or likely pathogenic (P/LP) variants. During a median follow-up of 15 months, 63 children (26.8%) died or underwent heart transplantation. Transplant-free survival did not differ significantly between P/LP-positive and genetic-negative groups (log-rank P = 0.058). Reduced ventricular function and late gadolinium enhancement were associated with adverse outcomes in univariable analyses. Among complete cases, the apparent C-index increased from 0.527 for demographics and cardiomyopathy phenotype to 0.813 after adding HF functional class and 0.842 after biomarkers, with limited additional discrimination from imaging measures. Conclusions Genetic testing demonstrated substantial laboratory-reported P/LP yield, although its effects on clinical management, family screening, and costs were not evaluated. HF functional severity and biomarkers provided the greatest apparent prognostic discrimination for death or transplantation, supporting an integrated clinical approach to pediatric cardiomyopathy assessment.