Clinical Characteristics and Electrophysiologic Properties of SCN5A Variants in Fever-Induced Brugada Syndrome

Background: Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome which can be unmasked by fever. Methods: A 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. Findings: 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. Compared with a historical cohort of non-fever BrS probands carrying SCN5A variants, carriers with fever-induced BrS were prone to MAE at 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. Interpretation: 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.  Funding Statement: The current work was supported by the National Natural Science Foundation Project of China (Grant No. 81670304); the National Institutes of Health of USA (NIH R56 - HL47678], NIH R01 [HL138103]), NIH R01 [HL152201], the W.W. Smith Charitable Trust and the Wistar and Martha Morris Fund. Declaration of Interests: The authors report no relationships that could be construed as a conflict of interest. Ethics Approval Statement: This study was approved by the Institutional Review Board of each hospital and performed in accordance with the declaration of Helsinki. All participants gave written informed consent.