Normal cardiac excitation and relaxation involves a delicate balance of complex dynamic interactions between ionic currents passing through a variety of membrane channels and the cellular environment. Genetic defects, polymorphisms, therapeutic intervention or structural abnormalities can disrupt this balance and underlie severe arrhythmogenic phenotypes that lead to sudden cardiac death. Inheritable gene defects give rise to phenotypic variation and an unpredictable manifestation of syndromes, ranging from silent gene carriers to profoundly symptomatic individuals, even within single families (1–7). As such, realizing the relationship between genetic mutations and clinical syndromes is becoming increasingly complex. In this issue of the JCI, Grant and colleagues (3) investigate the manifestations of phenotypically opposite and overlapping cardiac arrhythmogenic syndromes that surprisingly stem from the same mutation (1–4). Cardiac excitation reflects membrane depolarization of cardiac myocytes, primarily due to the activation of fast voltage-dependent Na+ channels that underlie the action potential upstroke. Activation is followed by a long depolarized plateau phase that permits Ca2+-induced Ca2+ release from the sarcoplasmic reticulum, binding of Ca2+ to contractile proteins on the sarcomeres, and coordinated contraction. Repolarization follows due to the timeand voltage-dependent activation of repolarizing potassium currents. Relaxation of contraction is coupled to the electrical repolarization phase, which allows filling of the ventricles prior to the next excitation. Each of these electrical processes can be detected on the body surface electrocardiogram (ECG) as a signal average of the temporal and spatial gradients generated during each phase (8–11)(Figure 1a). Electrical excitation gradients in the atria (atrial depolarization) manifest on the ECG as P waves, while gradients of ventricular depolarization are seen as the QRS complex. Gradients in ventricular repolarization are reflected in the T wave (Figure 1). A recently described example of a multi-syndrome genetic defect in the SCN5A gene, encoding the cardiac Na+ channel (Figure 2), is the insertion of an aspartic acid, 1795insD, in the C-terminus of the cardiac Na+ channel that underlies both Brugada (BrS) and Long-QT (LQTs) cardiac arrhythmic syndromes (1, 2).

Grant and colleagues investigate an even more complex mutation (3). The deletion of lysine,∆ K1500, in the III–IV linker of SCN5A (Figure 2) is associated with BrS, LQTs, and isolated cardiac conduction disease (ICCD). LQTs is typically associated with a gain of Na+ channel function that stems from mutation induced destabilization of