Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome,Human Mutation

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Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome
Human Mutation ( IF 3.3 ) Pub Date : 2020-11-01 , DOI: 10.1002/humu.24128
Charles M Pearman _{1,

2} , Nathan C Denham _{1,

2} , Robert W Mills ₃ , Wern Y Ding _{1,

4} , Simon S Modi ₁ , Mark C S Hall ₁ , Derick M Todd ₁ , Saagar Mahida _{1,

4}

Affiliation

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.

中文翻译：

Brugada 综合征相关 SCN5A 变异钠通道功能与临床表型的关系

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确定了与 BrS 相关的变体，关于通道功能和临床表型的数据在 142 中可用。在初步分析中，未发现通道功能的任何方面与 CA、VA/SCD 或自发 BrS ECG 模式之间存在关系。仅包括致病性或可能致病性分级变异的敏感性分析表明，峰值电流的减少和稳态激活的正向变化与 CA 和 VA/SCD 微弱相关，尽管敏感性和特异性仍然很低。通道功能的体外评估与 BrS 临床表型之间的关系较弱。渠道功能的评估并不能增强风险分层。将功能测试外推到变异致病性的可能性时需要谨慎。

更新日期：2020-11-27

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