BACKGROUND Mexiletine may protect patients with long QT syndrome (LQTS) type 3 from arrhythmias. However, we had found an unusual in utero presentation of intermittent atrioventricular block and ventricular tachycardia, spontaneous or lidocaine-induced, in a fetus and his sibling with LQTS. OBJECTIVE This study was to investigate the underlying channelopathy and functional alteration. METHODS Mutations were searched in KCNQ1, HERG, KCNE1, KCNE2, and SCN5A genes. In expressed mutants, whole-cell voltage clamp defined the electrophysiological properties. RESULTS Novel missense mutations involving hERG (F627L) at the pore region and SCN5A (R43Q) at the N-terminus were found in the proband and family members with prolonged QT interval. In oocytes injected with mRNA encoding hERG/ F627L, almost zero K+ currents were elicited and in co-injected oocytes, the currents were decreased to half. In tsA201 cells transfected with SCN5A/R43Q, though the baseline kinetics of the Na current was similar to wild type, lidocaine caused a unique hyperpolarizing shift of the activation and increased the availability of Na currents at resting voltages. The window currents were also enhanced due to a right shift of steady-state inactivation. These electrophysiological alterations after lidocaine may lead to the development of ventricular tachycardia. CONCLUSIONS We have identified a novel hERG/F627L mutation that results in LQTS with fetal onset of atrioventricular block and ventricular tachycardia. Besides, a coexisting SCN5A/R43Q variant, although it per se does not prolong repolarization, attributes the development of ventricular tachyarrhythmias after lidocaine. Patients with such latent lidocaine-induced phenotype given lidocaine or mexiletine may be at risk. KEYWORDS Congenital long QT syndrome; Atrioventricular block; Ventricular tachycardia; SCN5A; hERG; Mutation; Variant; Lidocaine