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

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 samemutation was found in 6 family members of which 2 had very mild symptoms and 4 were completely asymptomatic. In genetic terms, this mutation shows incomplete penetrance and variable expressivity. Penetrance describes the extent to which the properties controlled by a gene, its phenotype,will be expressed. In case of high penetrance, the mutation or gene always leads to a certain phenotype. Conversely, if penetrance is low or incomplete, the mutation only sporadically leads to a detectable phenotype.