Structural Heart Disease, SCN5A Gene Mutations, and Brugada Syndrome

Abstract

The report of the Second Consensus Conference, published in Circulation in 2005, defined the Brugada syndrome as ST-segment elevation in the right precordial ECG leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts.1 An autosomal dominant disease with incomplete penetrance, Brugada syndrome has been linked to mutations in SCN5A , the gene encoding the alpha subunit of the cardiac sodium channel.2 More than 80 mutations in SCN5A have been linked to this syndrome (references cited in Reference 1). Analysis of several of these mutations has consistently demonstrated a loss of function related to multiple mechanisms, including failure of sodium channel protein expression and changes in the voltage and time dependence of sodium channel current activation, inactivation, or reactivation.1 Still, SCN5A mutations have been reported in only &20% of patients with Brugada syndrome diagnosed on the basis of clinical criteria, suggesting that other genetic defects and/or other disease mechanisms may give rise to this clinical picture. To complicate matters further, SCN5A mutations have also been identified in patients with the long-QT syndrome. These mutations generally lead to a “gain of function” in the sodium channel, which prolongs the QT interval by increasing inward current. In fact, at least 3 human diseases have been linked to defects in this gene: Brugada syndrome, long-QT syndrome, and progressive conduction disturbances.2–4 Furthermore, there is considerable overlap of clinical profiles, so some patients with Brugada syndrome also have atrial fibrillation, conduction defects with sinus node abnormalities, or prolonged QT interval (reviewed in Reference 1). Thus, genotype-phenotype relationships in Brugada syndrome are highly complex and serve to underscore our incomplete knowledge of the pathogenesis of this type of inherited arrhythmogenic disease. Article p 3680 A similar area of increasing complexity and uncertainty has to …