Genetic testing in children with Brugada syndrome: results from a large prospective registry

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: None. BACKGROUND/INTRODUCTION: A pathogenic/likely pathogenic (P/LP) variant can be found in 20-25% of patients with Brugada syndrome (BrS) and a P/LP variant in SCN5A is associated with a worse prognosis. However, the diagnostic yield and the prognosis of gene testing in pediatric BrS syndrome is unclear. PURPOSE: The aim of this study is to define the diagnostic yield of SCN5A gene testing with ACMG standardized variant classification in a large cohort of pediatric BrS. Furthermore, a correlation between the clinical outcomes and the genetic background of children with BrS in comparison with adult BrS is aimed. METHODS: All consecutive patients diagnosed with BrS, between 1992 and 2022 were enrolled in a prospective monocentric registry. Inclusion criteria were: 1) BrS diagnosis; 2) Genetic analysis for SCN5A gene and 3) classification of gene variants following current ACMG guidelines. Pediatric patients were defined if ≤ 12 years of age. The primary endpoint was ventricular arrhythmias (VA) occurrence, defined as documented SCD, aborted SCD, ventricular tachycardia or ventricular fibrillation or appropriate ICD intervention. RESULTS: A total of 500 BrS patients were included, 41 pediatric patients and 459 adult patients. Among children with BrS, 19 patients (46.3%) had a P/LP variant (P+) in SCN5A gene. No P/LP variants could be identified in 22 (53.7%) pediatric patients (P-). After a mean follow-up of 140.2 months, 3 children (7.3%) experienced a VA, treated with appropriate ICD shock. Inappropriate shocks occurred in 3 pediatric patients (7.3%). At survival analysis, P- pediatric patients had higher VA free survival during the follow-up, compared with P+ pediatric patients (Log-Rank p=0.021), Figure 1. There was no difference in VA free survival between pediatric and adult BrS patients both without (P-), (Log-Rank p=0.19) and with (P+) a P/LP variant (Log-Rank p=0.91), Figure 2. CONCLUSION: In a large BrS cohort, the diagnostic yield for SCN5A P/LP variants in the pediatric population is 46.3%. P+ children with BrS have a worse arrhythmic prognosis. [Figure: see text] [Figure: see text]