A Novel SCN5A Variant Causes Temperature-Sensitive Loss Of Function in a Family with Symptomatic Brugada Syndrome, Cardiac Conduction Disease, and Sick Sinus Syndrome

Abstract

Introduction: Brugada syndrome (BrS) is an inherited arrhythmia syndrome associated with an increased risk of sudden cardiac death. SCN5A is the most important disease-modifying gene for BrS, but many SCN5A variants have not been functionally characterized. Furthermore, the temperature dependency of SCN5A is only rarely explored in in vitro analyses. Methods: The clinical phenotype of the affected family was assessed by medical history, ECGs and ajmaline challenge. Whole-cell patch clamp recordings were performed on HEK 293T cells expressing Nav1.5-G1712S, a novel SCN5A variant found in the symptomatic family. Results: Three male family members had experienced sudden cardiac death, sudden cardiac arrest, and rhythmogenic syncopes. Beside a positive ajmaline challenge with demarcation of a Brugada type 1 ECG, 1 patient also showed evidence of symptomatic cardiac conduction disease and sick sinus syndrome (SSS). In patch clamp analyses, Nav1.5-G1712S generated reduced peak currents as compared to the wild type. At body temperature, Nav1.5-G1712S additionally exhibited an enhanced slow inactivation and an impaired recovery from inactivation. Conclusion: We conclude that G1712S is a pathogenic SCN5A loss-of function mutation at physiological temperature associated with an overlapping presentation of BrS, SSS, and cardiac conduction disease.