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

Pearman, Charles M, Denham, Nathan C, Mills, Robert W, Ding, Wern Y ORCID: 0000-0003-3596-6545, Modi, Simon S, Hall, Mark CS, Todd, Derick M and Mahida, Saagar (2020) Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome. HUMAN MUTATION, 41 (12). pp. 2195-2204.

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Official URL: http://dx.doi.org/10.1002/humu.24128

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<sub>Na</sub> ) 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.

Item Type:	Article
Uncontrolled Keywords:	Brugada, patch clamp, risk stratification, sodium current
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User:	Symplectic Admin
Date Deposited:	01 Jul 2021 07:52
Last Modified:	18 Jan 2023 21:37
DOI:	10.1002/humu.24128
Open Access URL:	https://doi.org/10.1002/humu.24128
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3128380