Role of Rare and Common Genetic Variation in SCN5A in Cardiac Electrical Function and Arrhythmia

Barc, Julien; Bezzina, Connie R.

doi:10.1016/j.ccep.2014.07.001

Cited by 2 publications

(3 citation statements)

References 110 publications

(104 reference statements)

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“…13 For examples, gain-of-function SCN5A mutations may cause long QT syndrome type 3, whereas loss-of-function mutations may cause conduction disease, BrS, and sick sinus syndrome. 1,13,14 To complicate matters further, the same SCN5A mutation may also present differently even within the same family, for example, with features of long QT syndrome, BrS, and conduction disease, in a phenomenon now referred to as overlap syndromes. 15 Finally, common benign variants or single nucleotide polymorphisms can also potentially modulate phenotype severity by affecting both the biophysical properties of Na V 1.5 or its expression level.…”

Section: Discussionmentioning

confidence: 99%

“…15 Finally, common benign variants or single nucleotide polymorphisms can also potentially modulate phenotype severity by affecting both the biophysical properties of Na V 1.5 or its expression level. 13 …”

Section: Discussionmentioning

confidence: 99%

“…These findings raise the question whether patients with sinus node dysfunction, atrial arrhythmias, and poor pacemaker capture represent a unique clinical phenotype, early BrS, or whether they are part of this continuum in the spectrum of SCN5A overlap syndromes. 13,15 …”

Section: Discussionmentioning

confidence: 99%

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Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture

Chiang

Kim

Valdés

et al. 2015

Circ: Arrhythmia and Electrophysiology

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Background Cardiac device implantation can be complicated by inability to adequately place leads because of significant lead capture issues. This study sought to determine whether there are genetic bases that underlie poor lead capture. Methods and Results Retrospective review of all patients with structurally normal hearts who underwent new device implantation at Texas Children's Hospital between 2009 and 2014 was performed. Patients with inability to capture at 10 V or a final capture threshold ≥3 V at 0.4 ms during implant were analyzed. Among a total of 136 patients (median age, 13 years; range, 3 days to 46 years), 11 patients (8.1%) who underwent dual chamber device implantation had elevated thresholds in the atria (4), ventricle (3), or both chambers (4; atrial-lead threshold, 4.7±4.3 versus 0.7±0.3 V; ventricular-lead, 3.0±3.3 versus 0.7±0.3 V). All 11 patients presented with sinus node dysfunction and 10 had atrial arrhythmias. At implant, inability to find atrial capture was seen in 4 patients. Three demonstrated intermittent complete loss of ventricular capture after implantation: 1 has recurrent syncope, 2 eventually died. Genetic testing performed in 10 demonstrated 7 patients with 6 distinct SCN5A mutations, all predicted to be severe loss-of-function mutations by bioinformatic analyses. In the remaining patients, although putative pathogenic mutations were not found, multiple SCN5A polymorphisms were identified in 2 and a desmin mutation in 1. Conclusions This study suggests that significant capture issues at implant may be because of loss-of-function SCN5A mutations, providing new insights into SCN5A function. Recognition of this association may be critical for planning device implantation strategies and patient follow-up.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture

Chiang

Kim

Valdés

et al. 2015

Circ: Arrhythmia and Electrophysiology

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Cardiac Arrhythmias Related to Sodium Channel Dysfunction

Savio‐Galimberti

Argenziano

Antzelevitch

2017

Handbook of Experimental Pharmacology

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The voltage-gated cardiac sodium channel (Na1.5) is a mega-complex comprised of a pore-forming α subunit and 4 ancillary β-subunits together with numerous protein partners. Genetic defects in the form of rare variants in one or more sodium channel-related genes can cause a loss- or gain-of-function of sodium channel current (I) leading to the manifestation of various disease phenotypes, including Brugada syndrome, long QT syndrome, progressive cardiac conduction disease, sick sinus syndrome, multifocal ectopic Purkinje-related premature contractions, and atrial fibrillation. Some sodium channelopathies have also been shown to be responsible for sudden infant death syndrome (SIDS). Although these genetic defects often present as pure electrical diseases, recent studies point to a contribution of structural abnormalities to the electrocardiographic and arrhythmic manifestation in some cases, such as dilated cardiomyopathy. The same rare variants in SCN5A or related genes may present with different clinical phenotypes in different individuals and sometimes in members of the same family. Genetic background and epigenetic and environmental factors contribute to the expression of these overlap syndromes. Our goal in this chapter is to review and discuss what is known about the clinical phenotype and genotype of each cardiac sodium channelopathy, and to briefly discuss the underlying mechanisms.

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Role of Rare and Common Genetic Variation in SCN5A in Cardiac Electrical Function and Arrhythmia

Cited by 2 publications

References 110 publications

Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture

Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture

Cardiac Arrhythmias Related to Sodium Channel Dysfunction

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