Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome. Issue 12 (11th November 2020)

• Record Type: Journal Article
• Authors: Pearman, Charles M.; Denham, Nathan C.; Mills, Robert W.; Ding, Wern Y.; Modi, Simon S.; Hall, Mark C. S.; Todd, Derick M.; Mahida, Saagar
• Is Part Of: Human mutation. Volume 41:Issue 12(2020)
• Page Start: 2195
• Page End: 2204
• Publication Date: 2020-11-11
• Subjects: Brugada -- patch clamp -- risk stratification -- sodium current; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24128
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: The identification of a pathogenic SCN5A variant confers an increased risk of conduction defects and ventricular arrhythmias (VA) in Brugada syndrome (BrS). However, specific aspects of sodium channel function that influence clinical phenotype have not been defined. A systematic literature search identified SCN5A variants associated with BrS. Sodium current ( I Na ) functional parameters (peak current, decay, steady‐state activation and inactivation, and recovery from inactivation) and clinical features (conduction abnormalities [CA], spontaneous VA or family history of sudden cardiac death [SCD], and spontaneous BrS electrocardiogram [ECG]) were extracted. A total of 561 SCN5A variants associated with BrS were identified, for which data on channel function and clinical phenotype were 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. The relationship between in vitro assessment of channel function and BrS clinical phenotype is weak. The assessment of channel function does not enhance risk stratification. Caution is needed when extrapolating functional testing to the likelihood of variant pathogenicity. Abstract : A systematic review and meta‐analysis was performed of published SCN5A variants associated with Brugada syndrome to assess the relationship between in vitro effect on sodium channel function and clinical phenotype. The association was weak between a variant's in vitro effect and the incidence of spontaneous ventricular arrhythmias, conduction disease, or a spontaneous Type 1 ECG pattern.