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Background-Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identifcation of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results-We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identifed 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was signifcantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P, Circulation: Arrhythmia and Electrophysiology, 7(3), pp.511-517; 2014

We appreciated hearing from Casado-Arroyo et al regarding our recently published article, “Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated With Early Repolarization,” showing that SCN5A is a novel causative gene of early repolarization syndrome.1 In this study, we identified 3 SCN5A mutations in 3 unrelated patients with idiopathic ventricular fibrillation associated with early repolarization (or early repolarization syndrome). Because all of the patients had J-point elevation in the right precordial lead(s) in addition to J-point elevation in the inferior/lateral leads, Casado-Arroyo et al suggested that all of our patients have Brugada syndrome based on their recent findings that the risk of arrhythmia events is similar between patients with the Type 1 Brugada electrocardiographic pattern in 1 of the right precordial leads and patients with the Type 1 electrocardiographic pattern in >1 lead.2 However, we respectfully disagree because our patients never met the diagnostic criteria for Brugada syndrome.3 The diagnosis of Brugada syndrome is made when patients have a Type 1 Brugada electrocardiographic pattern, which is characterized by a prominent coved ST-segment elevation displaying a J-wave amplitude or ST-segment elevation ≥0.2 mV followed by a negative T-wave in ≥2 of the right precordial leads in the absence or presence of sodium channel blockers.3 Although the J-point elevation was ≥0.2 mV in 1 (Patients 2 and 3) or 2 (Patient 1) of the right …