Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Dec;41(12):2195-2204.
doi: 10.1002/humu.24128. Epub 2020 Nov 11.

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

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
Affiliations

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

Charles M Pearman et al. Hum Mutat. 2020 Dec.

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 (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.

Keywords: Brugada; patch clamp; risk stratification; sodium current.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there are no conflict of interests.

Figures

Figure 1
Figure 1
Association with spontaneous ventricular arrhythmias (VA) or family history of sudden cardiac death (SCD). (a–c) Beeswarm plots. Each point represents anSCN5Avariant plotted against peak current (a), shift in steady‐state activation (b), and shift in steady‐state inactivation (c), stratified by association with VA/SCD. Horizontal bars represent group means. (d) Receiver operating characteristic curves of the same data. Dotted line represents no discrimination. (e) Location of variants on channel. Filled markers represent variants associated with VA/SCD.NS, not significant
Figure 2
Figure 2
Association with conduction system disease. (a–c) Beeswarm plots. Each point represents anSCN5Avariant plotted against peak current (a), shift in steady‐state activation (b), and shift in steady‐state inactivation (c), stratified by association with spontaneous ventricular arrhythmias or a family history of sudden cardiac death. Horizontal bars represent group means. (d) Receiver operating characteristic curves of the same data. Dotted line represents no discrimination. (e) Location of variants on channel. Filled markers represent variants associated with conduction disease. NS, not significant. *p < .05
Figure 3
Figure 3
Association with spontaneous type 1 Brugada ECG pattern. (a–c) Beeswarm plots. Each point represents anSCN5Avariant plotted against peak current (a), shift in steady‐state activation (b), and shift in steady‐state inactivation (c), stratified by association with spontaneous ventricular arrhythmias or a family history of sudden cardiac death. Horizontal bars represent group means. (d) Receiver operating characteristic curves of the same data. Dotted line represents no discrimination. (e) Location of variants on channel. Filled markers represent variants associated with spontaneous type 1 Brugada ECG pattern. ECG, electrocardiogram; NS, not significant
See this image and copyright information in PMC

References

    1. Amin, A. S. , Verkerk, A. O. , Bhuiyan, Z. A. , Wilde, A. A. , & Tan, H. L. (2005). Novel Brugada syndrome causing mutation in ion‐conducting pore of cardiac Na+ channel does not affect ion selectivity properties. Acta Physiologica Scandinavica, 185(4), 291–301. 10.1111/j.1365-201X.2005.01496.x - DOI - PubMed
    1. Baroudi, G. , Pouliot, V. , Denjoy, I. , Guicheney, P. , Shrier, A. , & Chahine, M. (2001). Novel mechanism for Brugada syndrome: Defective surface localization of an SCN5A mutant (R1432G). Circulation Research, 88(12), E78–E83. - PubMed
    1. Bezzina, C. R. , Barc, J. , Mizusawa, Y. , Remme, C. A. , Gourraud, J. B. , Simonet, F. , Verkerk, A. O. , Schwartz, P. J. , Crotti, L. , Dagradi, F. , Guicheney, P. , Fressart, V. , Leenhardt, A. , Antzelevitch, C. , Bartkowiak, S. , Borggrefe, M. , Schimpf, R. , Schulze‐Bahr, E. , Zumhagen, S. , … Redon, R. (2013). Common variants at SCN5A‐SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nature Genetics, 45(9), 1044–1049. 10.1038/ng.2712 - DOI - PMC - PubMed
    1. Campuzano, O. , Allegue, C. , Fernandez, A. , Iglesias, A. , & Brugada, R. (2015). Determining the pathogenicity of genetic variants associated with cardiac channelopathies. Scientific Reports, 5, 7953 10.1038/srep07953 - DOI - PMC - PubMed
    1. Campuzano, O. , Sarquella‐Brugada, G. , Fernandez‐Falgueras, A. , Cesar, S. , Coll, M. , Mates, J. , Arbelo, E. , Perez‐Serra, A. , del Olmo, B. , Jordá, P. , Fiol, V. , Iglesias, A. , Puigmulé, M. , Lopez, L. , Pico, F. , Brugada, J. , & Brugada, R. (2019). Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. Human Mutation, 40, 749–764. 10.1002/humu.23730 - DOI - PubMed

Publication types

MeSH terms

Substances