Enhanced impact of SCN5A mutation associated with long QT syndrome in fetal splice isoform

Congenital long QT syndrome (LQTS) is an inherited syndrome characterized by prolongation of the QT interval on the electrocardiogram and an increased susceptibility to life-threatening ventricular arrhythmias. Mutations in the SCN5A gene, which encodes the α-subunit of the cardiac Na+ channel, represent the third most common cause of LQTS, behind mutations in potassium channel genes KCNQ1 and KCNH2. Moreover, mutations in SCN5A have been linked to other types of inherited channelopathies, including the Brugada syndrome (BRS1), progressive familial heart block type 1 (PFHBI), sick sinus syndrome type 1 (SSS1), idiopathic ventricular fibrillation (IVF), familiar atrial standstill, dilated cardiomyopathy type 1E (CMD1E), and sudden infant death syndrome (SIDS)1. In total, more than 400 unique DNA variants have been reported in SCN5A, of which at least more than 80 mutations were linked to LQTS alone (see inherited arrhythmia data base: http:// www.fsm.it/cardmoc/).