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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."xsd:string
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http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/author"Leffler A."xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/author"Veltmann C."xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/author"Duncker D."xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/author"Mueller-Leisse J."xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/author"Sanner K."xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/author"Zormpas C."xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/name"Cardiology"xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/pages"754-762"xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/title"A Novel SCN5A Variant Causes Temperature-Sensitive Loss Of Function in a Family with Symptomatic Brugada Syndrome, Cardiac Conduction Disease, and Sick Sinus Syndrome."xsd:string
http://purl.uniprot.org/citations/34348284http://purl.uniprot.org/core/volume"146"xsd:string
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