Carrying multiple genetic variants significantly increased the risk of cardiac events in pediatric early-onset cardiomyopathies compared with a single variant (HR 7.27; 95% CI 2.47-21.44; P<.001).
Cohort (n=84)
No
Does a higher genetic burden (multiple genetic variants) increase the risk of cardiac events in pediatric patients with early-onset nonsyndromic cardiomyopathies?
In pediatric early-onset nonsyndromic cardiomyopathies, carrying multiple genetic variants is associated with a more than 7-fold increased risk of major cardiac events compared to carrying a single causal variant.
Effect estimate: HR 7.27 (95% CI 2.47-21.44)
p-value: p=<.001
INTRODUCTION AND OBJECTIVES Early-onset nonsyndromic cardiomyopathies (eoNSCM) are rare in pediatrics and are often associated with cardiac events (CE). The prognostic impact of multiple genetic variants in eoNSCM remains incompletely characterized. This study aimed to describe clinical outcomes in a pediatric cohort with eoNSCM and to analyze their association with genetic burden. METHODS Single-center retrospective study analyzing clinical and genetic data from patients with eoNSCM. The primary outcome was the occurrence of CE: ventricular tachycardia or fibrillation, appropriate implantable cardioverter-defibrillator shocks, cardiac arrest or sudden cardiac death, heart failure stages C and D, or heart transplantation. RESULTS From 2014 to 2024, 202 pediatric patients were evaluated for cardiomyopathy, of whom 84 were diagnosed with eoNSCM (36.9% female; median age at onset, 13 interquartile range, 2.5-15 years. Diagnoses included 53 hypertrophic cardiomyopathies (63%), 21 dilated cardiomyopathies (25%), and 10 arrhythmogenic cardiomyopathies (12%). A conclusive genetic diagnosis was obtained in 52 of 84 (62%). Twenty-four patients (29%) experienced a significant CE, of whom 19 of 24 (79%) carried multiple genetic variants. Children with multiple variants exhibited a significantly higher risk of CE compared with carriers of a single causal variant (HR, 7.27; 95%CI, 2.47-21.44; P < .001). The highest risk was observed in patients carrying 2 pathogenic or likely pathogenic variants (P < .001). In dilated cardiomyopathy, adding baseline phenotype (left ventricular dilation and systolic dysfunction) to a genetics-only model improved discrimination for CE (integrated discrimination improvement, 0.528; 95%CI, 0.312-0.683; P < .001). CONCLUSIONS Pediatric eoNSCM shows a high prevalence of rare variants. In this cohort, a higher genetic burden was associated with an increased risk of CE.
Greco et al. (Sun,) conducted a cohort in Early-onset nonsyndromic cardiomyopathies (n=84). Multiple genetic variants vs. Single causal variant was evaluated on Occurrence of cardiac events (ventricular tachycardia or fibrillation, appropriate implantable cardioverter-defibrillator shocks, cardiac arrest or sudden cardiac death, heart failure stages C and D, or heart transplantation) (HR 7.27, 95% CI 2.47-21.44, p=<.001). Carrying multiple genetic variants significantly increased the risk of cardiac events in pediatric early-onset cardiomyopathies compared with a single variant (HR 7.27; 95% CI 2.47-21.44; P<.001).