SCN5A (Na V 1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance

Brett M Kroncke; Andrew M Glazer; Derek K Smith; Jeffrey D Blume; Dan M Roden

doi:10.1161/CIRCGEN.118.002095

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SCN5A (Na V 1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance

Journal article

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Peer reviewed

SCN5A (Na V 1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance

Brett M Kroncke, Andrew M Glazer, Derek K Smith, Jeffrey D Blume and Dan M Roden

Circulation. Genomic and precision medicine, Vol.11(5), pp.e002095-e002095

05/2018

DOI: 10.1161/CIRCGEN.118.002095

PMCID: PMC5941942

PMID: 29728395

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Abstract

Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel (protein Na 1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance. From a comprehensive literature review, we quantified the number of carriers presenting with and without disease for 1712 reported variants. For 356 variants, data were also available for 5 Na 1.5 electrophysiological parameters: peak current, late/persistent current, steady-state V1/2 of activation and inactivation, and recovery from inactivation. We found that peak and late current significantly associate with Brugada syndrome ( <0.001; ρ=-0.44; Spearman rank test) and long QT syndrome disease penetrance ( <0.001; ρ=0.37). Steady-state V1/2 activation and recovery from inactivation associate significantly with Brugada syndrome and long QT syndrome penetrance, respectively. Continuous estimates of disease penetrance align with the current American College of Medical Genetics classification paradigm. Na 1.5 in vitro electrophysiological parameters are correlated with Brugada syndrome and long QT syndrome disease risk. Our data emphasize the value of in vitro electrophysiological characterization and incorporating counts of affected and unaffected carriers to aid variant classification. This quantitative analysis of the electrophysiological literature should aid the interpretation of Na 1.5 variant electrophysiological abnormalities and help improve Na 1.5 variant classification.

Brugada syndrome

electrophysiology

long QT syndrome

ion channels

penetrance

Details

Title: Subtitle: SCN5A (Na V 1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance
Creators: Brett M Kroncke - Giesecke and Devrient
Andrew M Glazer - Giesecke and Devrient
Derek K Smith - Vanderbilt University Medical Center
Jeffrey D Blume - Vanderbilt University Medical Center
Dan M Roden - United States Nuclear Regulatory Commission
Resource Type: Journal article
Publication Details: Circulation. Genomic and precision medicine, Vol.11(5), pp.e002095-e002095
DOI: 10.1161/CIRCGEN.118.002095
PMID: 29728395
PMCID: PMC5941942
NLM abbreviation: Circ Genom Precis Med
ISSN: 2574-8300
eISSN: 2574-8300
Grant note: P50 GM115305 / NIGMS NIH HHS R01 HL118952 / NHLBI NIH HHS F32 HL137385 / NHLBI NIH HHS K99 HL135442 / NHLBI NIH HHS
Language: English
Date published: 05/2018
Academic Unit: Preventive and Community Dentistry; Dental Research
Record Identifier: 9984966755102771

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