Genetic Testing in Brugada Syndrome: A 30-Year Experience

A pathogenic/likely pathogenic variant can be found in 20% to 25% of patients with Brugada syndrome (BrS) and a pathogenic/likely pathogenic variant in SCN5A is associated with a worse prognosis. The aim of this study is to define the diagnostic yield of a large gene panel with American College of Medical Genetics and Genomics variant classification and to assess prognosis of SCN5A and non-SCN5A variants.

All patients with BrS, were prospectively enrolled in the Universitair Ziekenhuis Brussel registry between 1992 and 2022. Inclusion criteria for the study were (1) BrS diagnosis; (2) genetic analysis performed with a large gene panel; (3) classification of variants following American College of Medical Genetics and Genomics guidelines. Patients with a pathogenic/likely pathogenic variant in SCN5A were defined as SCN5A⁺. Patients with a reported variant in a non-SCN5A gene or with no reported variants were defined as patients with SCN5A^-. All variants were classified as missense or predicted loss of function.

A total of 500 BrS patients were analyzed. A total of 104 patients (20.8%) were SCN5A⁺ and 396 patients (79.2%) were SCN5A^-. A non-SCN5A gene variant was found in 75 patients (15.0%), of whom, 58 patients (77.3%) had a missense variant and 17 patients (22.7%) had a predicted loss of function variant. At a follow-up of 84.0 months, 48 patients (9.6%) experienced a ventricular arrhythmia (VA). Patients without any variant had higher VA-free survival, compared with carriers of a predicted loss of function variant in SCN5A⁺ or non-SCN5A genes. There was no difference in VA-free survival between patients without any variant and missense variant carriers in SCN5A⁺ or non-SCN5A genes. At Cox analysis, SCN5A⁺ or non-SCN5A predicted loss of function variant was an independent predictor of VA.

In a large BrS cohort, the yield for SCN5A⁺ is 20.8%. A predicted loss of function variant carrier is an independent predictor of VA.