Relationship Between Sodium Channel Function and Clinical Phenotype in SCN5A Variants Associated with Brugada syndrome

Introduction
Identification of a pathogenic SCN5A variant confers an increased risk of conduction defects and ventricular arrhythmias in Brugada syndrome (BrS). However, specific aspects of sodium channel function that influence clinical phenotype have not been defined.
Methods
A systematic literature search identified SCN5A variants associated with BrS. Sodium current (INa) functional parameters (peak current, decay, steady-state activation and inactivation, recovery from inactivation) and clinical features (conduction abnormalities (CA), spontaneous ventricular arrhythmias or family history of sudden death (VA/SCD), and spontaneous BrS ECG) were extracted.
Results
561 SCN5A variants associated with BrS were identified, for which data on channel function and clinical phenotype was available in 142. In the primary analysis, no relationship was found between any aspect of channel function and CA, VA/SCD or spontaneous BrS ECG pattern. Sensitivity analyses including only variants graded pathogenic or likely pathogenic suggested that reduction in peak current and positive shift in steady state activation were weakly associated with CA and VA/SCD, although sensitivity and specificity remained low.
Conclusions
The relationship between in vitro assessment of channel function and BrS clinical phenotype is weak. Assessment of channel function does not enhance risk stratification. Caution is needed when extrapolating functional testing to likelihood of variant pathogenicity.