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).
1
,2
In 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.
3
,4
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Article info
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Published online: February 27, 2023
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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.
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