Cardiovascular Genetics Diseases Prize Finalists (012–015)
Arrhythmias are a Requisite Feature of SCN5A Mediated Dilated Cardiomyopathy: A Systematic Review of Variants

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Purpose

Variants in SCN5A, the gene that encodes the cardiac sodium channel, Nav1.5, are associated with a highly arrhythmogenic form of dilated cardiomyopathy (DCM). The purpose of this study was to review the phenotypes, natural history, functional effects, and treatment outcomes of DCM-associated rare SCN5A variants.

Methods

A systematic review of published DCM-associated rare SCN5A variants was conducted using PubMed and Embase.

Results

18 SCN5A rare variants in 29 families with DCM (173 affected individuals) were identified. Eight variants, seven located in transmembrane voltage-sensing domains, had experimental evidence of gain-of-function (GOF) effects on Nav1.5 activation. There were only three variants with loss-of-function effects, and seven were uncharacterised. The GOF phenotype included frequent multiform ventricular premature beats (70% of affected relatives), ventricular arrhythmias (33%), atrial arrhythmias (30%),

Conclusions

Most DCM-associated SCN5A variants have GOF effects and an arrhythmia-predominant phenotype that is reversible with Nav1.5 inactivation. Our findings have implications for interpretation and management of SCN5A variants found in DCM patients with and without arrhythmias.

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