Background
Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome which can be unmasked by fever.
Objective
To describe the clinical features and unique characteristics of SCN5A mutations contributing to the development off ever-induced BrS.
Methods
The clinical analysis was performed in 134 probands diagnosed with fever-induced BrS, including 59 patients who received next-generation genetic sequencing. We employed a biophysics-based computational protocol to investigate whether protein structure destabilization contributes to Nav1.5 variant-mediated fever-induced BrS.
Results
Among all cases enrolled, the symptoms at diagnosis were syncope in 26 (19.40%) and major arrhythmic events (MAE) in 16 (11.94%). SCN5A variant carriers were significantly younger than probands free of SCN5A variants. Multivariate analysis indicated that younger age, Caucasian ethnicity, family history of SCD, and wider Tpeak-Tend interval were independent predictors of MAE. Compared with a historical cohort of non-fever BrS probands carrying SCN5A variants, carriers with fever-induced BrS were prone to MAE at a younger age, and had a higher proportion of variants localizing at the interdomain linkers. Modeling result showed that most variants are destabilizing when temperature increases, suggesting that Nav1.5 structure destabilization is the cause of fever-induced BrS associated with SCN5A variants.
Conclusion
In our cohort, SCN5A variant carriers with fever-induced BrS present at a younger age and harbor SCN5A variants predominantly localized to interdomain linker regions of Nav1.5. These SCN5A variants typically induce destabilization of Nav1.5 structure at higher body temperatures. Patients with SCN5A mutations present within interdomain linker regions may warrant more aggressive monitoring and management of fever.
Article info
Identification
Copyright
© 2021 Published by Elsevier Inc.
