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

Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1105-12. doi: 10.1161/CIRCEP.115.003098. Epub 2015 Jun 25.


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.

Keywords: Brugada syndrome; NaV1.5 voltage-gated sodium channel; SCN5A protein, human; atrial tachyarrhythmia with short PR; cardiac pacemaker, artificial; implantable cardioverter-defibrillators; sick sinus syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / therapy
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Mutation / genetics*
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • Pacemaker, Artificial*
  • Retrospective Studies
  • Sick Sinus Syndrome / genetics*
  • Sick Sinus Syndrome / physiopathology
  • Sick Sinus Syndrome / therapy


  • NAV1.5 Voltage-Gated Sodium Channel