Cardiac Sodium Channel Gene Variants and Sudden Cardiac Death in Women

Our present ability to identify individuals who are at risk for sudden cardiac death (SCD) in the general population is poor. Although SCD risk has a heritable component, our understanding of the genetic basis of SCD is most advanced in rare arrhythmic disorders such as the long-QT and Brugada syndromes, in which mutations in genes encoding cardiac ion channels result in increased susceptibility for SCD. The extent to which the heritable component of more common forms of SCD might be due to similar mutations or rare polymorphisms in these same genes is currently unknown. To address this question, we determined both the prevalence and function of mutations and rare coding sequence variants in 5 cardiac ion channel genes among 113 unselected cases of SCD drawn from 2 large prospective cohorts of women and men. No mutations or rare variants were identified in any of the 53 subjects who were men. In contrast, 2 mutations and 3 rare missense variants in a single ion channel gene, the cardiac sodium channel SCN5A, were found in 6 of 60 women (10%), and all but 1 resulted in significantly shorter recovery times from channel inactivation. The overall frequency of these rare variants in SCN5A was significantly higher in the SCD cases (6/60, 10.0%) compared with controls (12/733, 1.6%; P 0.001) from the same population. These data suggest that functionally significant rare variants in SCN5A may contribute to SCD risk in the general population and particularly among women. See p 16.