Penetrance of monogenetic cardiac conduction diseases. A matter of conduction reserve?

Abstract

See article by Tan et al. [3] (pages 409–417) in this issue. Loss-of-function mutations in the SCN5a gene coding for the human Nav1.5 cardiac sodium channel, which lead to decreased peak sodium current, are associated with cardiac conduction defects (CCD), progressive cardiac conduction disease [1] or Brugada syndrome [2]. However, despite the strong linkage of sodium channel mutations to the disease in probands, the same mutation is often found in non-affected family members. The study by Tan and coworkers in this issue describes a SCN5a mutation leading to a C-terminal truncation (L1821fs/10) that was found in a patient with sick sinus syndrome, CCD and ventricular tachycardia [3]. This particular mutation was shown to lead to an almost complete loss of channel function and thus to haploinsufficiency of the peak sodium current. Interestingly, the same mutation was found in 6 family members of which 2 had very mild symptoms and … *Corresponding author. Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, The Netherlands. Tel.: +31 30 253 8900; fax: +31 30 253 9036. h.v.m.vanrijen{at}med.uu.nl