Refining the genotype-phenotype correlation in Brugada syndrome – is there a role for in vitro functional testing of sodium channel function?

Background: Individuals with Brugada syndrome (BrS) in whom a variant can be found in SCN5A, the gene encoding the alpha subunit of the cardiac sodium channel, have a more marked phenotype. However, many SCN5A variants have little apparent effect on the sodium current INa. We asked whether in vitro functional assessment of SCN5A variants could refine the genotype-phenotype correlation. Methods: A systematic literature search was performed to identify SCN5A variants associated with BrS. Details were extracted for channel function obtained from patch clamp recordings in cell lines expressing mutant channels (peak current, steady-state activation and inactivation, recovery from inactivation and current decay) as were clinical features (cardiac conduction disturbances including atrioventricular block and sinus node dysfunction, the composite of spontaneous ventricular arrhythmias or family history of sudden death (VA/SCD), and spontaneous BrS ECG pattern). Receiver operating characteristic (ROC) curves were constructed to evaluate area under the curve (AUC) and optimal cut-offs for continuous variables. Results: Ninety-three SCN5A variants were identified for which robust in vitro and clinical characterisation was available. Variants associated with conduction abnormalities had greater INa reduction (conduction abnormalities 75.5 ± 5.9%, no conduction abnormalities 53.8 ± 5.3%, p