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Catecholaminergic polymorphic ventricular tachycardia : a clinical and genetic analysis of pediatric patients based on age Kallas, Dania


Rationale: The relationship between age of symptom-onset and disease course is currently unknown in pediatric Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) patients. We aim to compare clinical characteristics and screen for genetic modifiers based on age at symptom-onset in pediatric CPVT patients diagnosed <19 years of age. Methods: A retrospective, multicenter, international cohort of pediatric CPVT patients was categorized as early-onset (EOP; symptom-onset <10 years) or adolescent-onset (AOP; symptom-onset 10-18 years inclusive). Demographics, clinical tests, therapy, genetics and outcomes were compared among groups. A next-generation sequencing approach of 71 genes were used to screen for potential genetic modifiers among early and adolescent-onset CPVT trios. Results: We included 58 EOP and 76 AOP in our clinical characterization. Median age at symptom-onset was 6 (IQR: 4-8) years for EOP and 13 (IQR: 11-15) years for AOP. Implantable cardioverter-defibrillator (ICD) use for primary prevention was higher in EOP (n=10/23, 44%) versus AOP (n=3/26, 12%) (p=0.02). De novo variants were more frequent in EOP (n=24/35, 69%) than AOP (n=12/40, 30%) in 75 trios (p=0.001). Proband status was an independent predictor of early-onset disease (p=0.01, OR=16.56, 95% CI=1.91-143.80). Over a median follow-up of 6 (IQR: 3-10) and 7 (IQR: 3-19.75) years after symptom-onset, 24 (41%) EOP and 21 (28%) AOP experienced cardiac events (p=0.037), respectively, including 4 sudden cardiac deaths in EOP versus none in AOP. Proband status was an independent predictor of time to first cardiac event (p=0.007, HR=4.59, 95% CI=1.53-13.80). In a group of 11 trios, there was no difference in the total number of variants and deleterious variants between EOP and AOP (p=0.99). ANK2 was the only gene in which all variants categorized to one group (EOP) and all variants were rare (p.Val1486Leu, p.Glu1449Gly and p.Thr3062del). Conclusion: Proband status rather than age at symptom-onset is a predictor of early-onset disease and an earlier-onset of cardiac events after diagnosis. Genetic factors may contribute to risk in early-onset CPVT. ANK2 showed high susceptibility as a modifier gene for early-onset CPVT, however, further research in a larger cohort is needed to verify this finding.

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