Disease-causative variants in the SCN5A-encoded pore-forming α subunit of the Nav1.5 cardiac sodium channel cause a spectrum of electrical and structural genetic heart disorders including type 1 Brugada syndrome (BrS1; Nav1.5 loss-of-function), type 3 long QT syndrome (LQT3; Nav1.5 gain-of-function), multifocal ectopic Purkinje-related premature contractions (Nav1.5 gain-of-function), progressive cardiac conduction disease (PCCD; Nav1.5 loss-of-function), and dilated cardiomyopathy (Nav1.5 loss-of-function, gain-of-function, and overlapping functional effects).
- Giudicessi J.R.
- Ackerman M.J.
Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes.
Transl Res. 2013; 161: 1-14
2In addition, so-called SCN5A overlap syndromes, whereby the clinical and electrocardiographic features of more than one of the above disorders (eg, BrS1 plus LQT3 or LQT3 plus multifocal ectopic Purkinje-related premature contractions), are not infrequently observed in a single SCN5A variant–positive individual or across family members with the same disease-causative SCN5A variant.
- Wilde A.A.M.
- Amin A.S.
Clinical spectrum of SCN5A mutations: long QT syndrome, Brugada syndrome, and cardiomyopathy.
JACC Clin Electrophysiol. 2018; 4: 569-579
- Makita N.
- Behr E.
- Shimizu W.
- et al.
The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.
J Clin Invest. 2008; 118: 2219-2229
- Barake W.
- Giudicessi J.R.
- Asirvatham S.J.
- Ackerman M.J.
Purkinje system hyperexcitability and ventricular arrhythmia risk in type 3 long QT syndrome.
Heart Rhythm. 2020; 17: 1768-1776
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- Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes.Transl Res. 2013; 161: 1-14
- Clinical spectrum of SCN5A mutations: long QT syndrome, Brugada syndrome, and cardiomyopathy.JACC Clin Electrophysiol. 2018; 4: 569-579
- The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.J Clin Invest. 2008; 118: 2219-2229
- Purkinje system hyperexcitability and ventricular arrhythmia risk in type 3 long QT syndrome.Heart Rhythm. 2020; 17: 1768-1776
- Further insights in the most common SCN5A mutation causing overlapping phenotype of long QT syndrome, Brugada syndrome, and conduction defect.J Am Heart Assoc. 2016; 5e003379
- Systematic ajmaline challenge in patients with long QT 3 syndrome caused by the most common mutation: a multicentre study.Europace. 2017; 19: 1723-1729
- An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.Heart Rhythm. 2010; 7: 33-46
- SCN5A mutation type and a genetic risk score associate variably with Brugada syndrome phenotype in SCN5A families.Circ Genom Precis Med. 2020; 13e002911
- Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death.Nat Genet. 2013; 45: 1044-1049
- PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.Nat Commun. 2018; 9: 2904
- Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.Nat Genet. 2014; 46: 826-836
- Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.Nat Genet. 2010; 42: 1068-1076
- Standing genetic variation affects phenotypic heterogeneity in a SCN5A-mutation founder population with excess sudden cardiac death.Heart Rhythm. 2023; (XX:XX–XX)
- Echocardiography-guided risk stratification for long QT syndrome.J Am Coll Cardiol. 2020; 76: 2834-2843
Published online: February 27, 2023
Publication stageIn Press Journal Pre-Proof
Funding Sources: The author has no funding sources to disclose.
Disclosures: The author has no conflicts of interest to disclose.
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- Standing genetic variation affects phenotypic heterogeneity in an SCN5A-mutation founder population with excess sudden cardiac deathHeart Rhythm
- PreviewThe Worm Study, ascertained from a multigeneration pedigree segregating a single amino acid deletion in SCN5A (c.4850_4852delTCT, p.(Phe1617del), rs749697698), is characterized by substantial phenotypic heterogeneity and overlap of sudden cardiac death, long-QT syndrome, cardiac conduction disease, Brugada syndrome, and isorhythmic atrioventricular dissociation. Linkage analysis for a synthetic trait derived from these phenotypes identified a single peak (logarithm of the odds [LOD] = 4.52) at the SCN5A/SCN10A/SCN11A locus on chromosome 3.