Key result
In vitro SCN5A function fails to predict arrhythmia risk or clinical phenotype in Brugada syndrome.
Why the study?
Pathogenic SCN5A variants increase the risk of conduction defects and ventricular arrhythmias in Brugada syndrome, but the specific aspects of sodium channel function influencing clinical phenotype have not been defined.
Does in vitro assessment of sodium channel function correlate with clinical phenotype in SCN5A variants associated with Brugada syndrome?
Systematic Review (n=142)
Does in vitro assessment of sodium channel function correlate with clinical phenotype in SCN5A variants associated with Brugada syndrome?
In vitro assessment of sodium channel function in SCN5A variants associated with Brugada syndrome correlates weakly with clinical phenotype and does not enhance clinical risk stratification.
Answers are grounded in this paper and cite their sources.
In vitro SCN5A function assessment does not improve risk stratification in Brugada syndrome; challenges assumptions of direct channel-phenotype correlation.
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 (INa) 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.
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Pearman et al. (2020) conducted a systematic review in Brugada syndrome (n=142). SCN5A variant in vitro channel function vs. Unexposed/wild-type or different clinical phenotypes was evaluated on Association between sodium channel functional parameters and conduction abnormalities, ventricular arrhythmias/sudden cardiac death, or spontaneous BrS ECG pattern. In a systematic analysis of SCN5A variants associated with Brugada syndrome, no significant relationship was found between in vitro sodium channel function and the risk of conduction abnormalities, ventricular arrhythmias, or spontaneous Brugada ECG pattern.
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