Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy

JACC Clin Electrophysiol. 2018 May;4(5):569-579. doi: 10.1016/j.jacep.2018.03.006. Epub 2018 May 2.


SCN5A gene encodes the pore-forming ion-conducting α-subunit of the cardiac sodium channel (Nav1.5), which is responsible for the initiation and propagation of action potentials and thereby determines cardiac excitability and conduction of electrical stimuli through the heart. The importance of Nav1.5 for normal cardiac electricity is reflected by various disease entities that can be caused by mutations in SCN5A. Gain-of-function mutations in SCN5A lead to more sodium influx into cardiomyocytes through aberrant channel gating and cause long QT syndrome, a primary electrical disease of the heart. Loss-of-function mutations in SCN5A lead to lower expression levels of SCN5A or production of defective Nav1.5 proteins and cause Brugada syndrome, an electrical disease with minor structural changes in the heart. In addition, both loss- and gain-of-function mutations may cause dilated cardiomyopathy, which is an arrhythmogenic disease with gross structural defects of the left ventricle (and sometimes both ventricles). Other SCN5A-related diseases are multifocal ectopic premature Purkinje-related complexes (gain-of-function mutations), isolated cardiac conduction defect (loss-of-function mutations), sick sinus syndrome (loss-of-function mutations), atrial fibrillation (loss-of-function or gain-of-function mutations), and overlap syndromes (mutations with both loss-of-function and gain-of-function effects). Growing insights into the role of SCN5A in health and disease has enabled clinicians to lay out gene-specific risk stratification schemes and mutation-specific diagnostic and therapeutic strategies in the management of patients with a SCN5A mutation. This review summarizes currently available knowledge about the pathophysiological mechanisms of SCN5A mutations and describes how this knowledge can be used to manage patients suffering from potentially lethal cardiac diseases.

Keywords: Brugada syndrome; SCN5A; dilated cardiomyopathy; long QT syndrome; mutation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Brugada Syndrome* / genetics
  • Brugada Syndrome* / physiopathology
  • Brugada Syndrome* / therapy
  • Cardiomyopathies* / genetics
  • Cardiomyopathies* / physiopathology
  • Cardiomyopathies* / therapy
  • Humans
  • Long QT Syndrome* / genetics
  • Long QT Syndrome* / physiopathology
  • Long QT Syndrome* / therapy
  • Mutation / genetics
  • NAV1.5 Voltage-Gated Sodium Channel* / genetics
  • NAV1.5 Voltage-Gated Sodium Channel* / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel* / physiology


  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human