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Aims A pathogenic/likely pathogenic (P/LP) variant in SCN5A is found in 20–25% of patients with Brugada syndrome (BrS). However, the diagnostic yield and prognosis of gene panel testing in paediatric BrS is unclear. The aim of this study is to define the diagnostic yield and outcomes of SCN5A gene testing with ACMG variant classification in paediatric BrS patients compared with adults. Methods and results All consecutive patients diagnosed with BrS, between 1992 and 2022, were prospectively enrolled in the UZ Brussel BrS registry. Inclusion criteria were: (i) BrS diagnosis; (ii) genetic analysis performed with a large gene panel; and (iii) classification of gene variants following ACMG guidelines. Paediatric patients were defined as ≤16 years of age. The primary endpoint was ventricular arrhythmias (VAs). A total of 500 BrS patients were included, with 63 paediatric patients and 437 adult patients. Among children with BrS, 29 patients (46%) had a P/LP variant (P+) in SCN5A and no variants were found in 34 (54%) patients (P−). After a mean follow-up of 125.9 months, 8 children (12.7%) experienced a VA, treated with implanted cardioverter defibrillator shock. At survival analysis, P− paediatric patients had higher VA-free survival during the follow-up, compared with P+ paediatric patients. P+ status was an independent predictor of VA. There was no difference in VA-free survival between paediatric and adult BrS patients for both P− and P+. Conclusion In a large BrS cohort, the diagnostic yield for P/LP variants in the paediatric population is 46%. P+ children with BrS have a worse arrhythmic prognosis.

Funding Acknowledgements Type of funding sources: None. Background/introduction Brugada syndrome (BrS) is associated with ventricular arrhythmias (VA) in macroscopically normal hearts. VA in BrS can be classified as ventricular fibrillation (VF) and monomorphic ventricular tachycardia (MVT). Although BrS has been initially described in association with VF, MVT is not rare, as it occurs in ≈30% of BrS patients. Purpose The aim of this study is to correlate VF or MVT with the genetic background and other clinical variables. Methods All BrS patients, were prospectively enrolled in a monocentric registry between 1992 and 2022. Inclusion criteria for the study were: 1) BrS diagnosis; 2) Genetic analysis performed for SCN5A; 3) Classification of variants following ACMG guidelines. Patients with a pathogenic/likely pathogenic (P/LP) variant in SCN5A were defined as (P+). Patients without a P/LP variant were defined as (P-). Primary endpoint was VA occurrence, defined as: documented arrhythmic SCD, documented arrhythmic aborted SCD, VF, sustained MVT or appropriate ICD intervention. All VA events were adjudicated as VF or MVT. Results A total of 500 BrS patients were analyzed. A P/LP variant in SCN5A was found in 104 patients (20.8%). After a mean follow-up of 110.9 months, 48 patients (9.6%) experienced a VA, adjudicated as MVT in 18 patients (37.5%) and VF in 30 patients (62.5%). At survival analysis, P- patients had higher VF free survival, compared with P+ patients (96.5% vs 84.6%, Log-Rank p<0.001) with no difference in MVT free survival (Log-Rank p=0.61), Figure 1. BrS patients > 30 years at diagnosis had higher VF free survival, compared with patients ≤ 30 years at diagnosis (95.5% vs 90.3%, Log-Rank p=0.041), with no difference in MVT free survival (Log-Rank p=0.9), Figure 2. Patients > 50 years at index event had higher VF free survival, compared with patients ≤ 50 years at index event (Log-Rank p=0.002), with no significant difference in MVT free survival (Log-Rank p=0.81). At Cox multivariate analysis independent predictors of VF occurrence were as follows: Age at index event ≤ 50 years (HR=2.57, CI 95% 1.01-6.6, p=0.04), P/LP variant in SCN5A (HR= 2.35, CI 95% 1.12-4.92, p=0.02), SND (HR= 2.67, CI 95% 1.01-7.04, p=0.044), history of syncope (HR= 2.14, CI 95% 1.02-4.51, p=0.047) and history of aborted SCD (HR= 18.66, CI 95% 8.87-39.27, p<0.001). Independent predictors of MVT occurrence were the following: history of syncope (HR= 2.71, CI 95% 1.26-5.80, p=0.01), history of aborted SCD (HR= 4.82, CI 95% 2.14-10.85, p<0.001), VA inducibility at EPS (HR= 3.71, CI 95% 1.66-8.31, p=0.001). Conclusion In a large BrS cohort undergoing genetic analysis MVT occurred in 37.5% of patients and VF in 62.5% of patients. P/LP SCN5A carriers and younger BrS population had a higher incidence of VF with no difference in MVT incidence.