Results From A Large Prospective Genetic Study In Children With Brugada Syndrome

Brugada syndrome (BrS) is an inherited arrhythmia syndrome that is associated with sudden cardiac death (SCD) and ventricular arrhythmias (VA). Pathogenic or likely pathogenic (P/LP) variants are found in 20-25% of BrS patients. P/LP variants in SCN5A indicate in the worse outcome. Nonetheless, the diagnostic yield and the prognosis of large gene panel testing in pediatric BrS has not been established. This study aims to define the diagnostic yield of a wide gene panel on a large cohort of pediatric BrS patients, based on the ACMG guidelines. An additional aim is to investigate the correlation between the clinical outcome and the genetic background in children with BrS as well as provide a comparison with adult BrS patients. A total of 452 patients, including 38 children and 414 adults, were enrolled in the UZ Brussel monocentric BrS registry, between 1992 and 2022. Inclusion criteria: BrS diagnosis, genetic analysis for BrS performed with a next generation sequencing-based large gene panel and recent re-classification of gene variants following current ACMG guidelines. Pediatric patients were defined as ≤ 12 years. The primary endpoint was VA occurrence, defined as documented SCD, aborted SCD, ventricular tachycardia or ventricular fibrillation or appropriate implanted cardioverter defibrillator (ICD) intervention. The diagnostic yield for P/LP variants in the pediatric population is 44.7% (P+), all present in the SCN5A gene, non in other BrS associated genes. After a mean follow-up of 142.7 months, 3 children (7.9%) experienced a VA, with appropriate ICD shocks. Inappropriate shocks occurred in 3 pediatric patients (7.9%). Pediatric patients without P/LP variants (P-) (55.3%) had higher VA free survival during the follow-up, compared with P+ pediatric patients. There was no difference in VA free survival between pediatric and adult BrS patients in both P- and P+ groups. P+ children with BrS have a worse arrhythmic prognosis.