Abstract
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Original language | English |
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Article number | e012374 |
Number of pages | 8 |
Journal | Circulation: Arrhythmia and Electrophysiology |
Volume | 17 |
Issue number | 4 |
DOIs | |
Publication status | Published - 1 Apr 2024 |
Bibliographical note
Funding Information:This research was funded by the Wetenschappelijk Fonds Willy Gepts of the Vrije Universiteit Brussel and Universitair Ziekenhuis Brussel through the projects Unraveling the molecular genetic pathways of Brugada syndrome via cardiomics research and The genetic complexity of Brugada syndrome: a multiple hit disease model?. RO is supported by the Bridge 2017: IGenCare: Integrated Personalised Medical Genomics Care Solution For Patients With Rare Genetic Diseases grant of Innoviris, Brussels.
Publisher Copyright:
© 2024 Lippincott Williams and Wilkins. All rights reserved.
Keywords
- Humans
- Brugada Syndrome/diagnosis
- Genetic Testing
- Arrhythmias, Cardiac/genetics
- Mutation, Missense
- NAV1.5 Voltage-Gated Sodium Channel/genetics
- Mutation