Abstract 2929: Cardiac Sodium Channel Mutations and Sudden Cardiac Death in Women
Background: Several cardiac ion channel genes have been implicated in monogenic traits with a high risk of sudden cardiac death (SCD). Mutations or rare variants in these genes have been proposed as potential contributors to more common forms of SCD, but this has not been systematically assessed.
Methods and Results: We directly sequenced the entire coding region and all splice junction sites of 5 cardiac ion channel genes, SCN5A, KCNQ1, KCNH2, KCNE1 and KCNE2, in 113 SCD cases from two large prospective cohorts of women (Nurses’ Health Study) and men (Health Professional Follow-up Study). Controls from the same population were then screened for the presence of mutations or rare variants identified in cases, and sequence variants without prior functional data were expressed in Xenopus oocytes to assess their biophysical consequences. No mutations or rare variants were identified in any of the 53 male subjects. In contrast, in 6 out of 60 women (10%), we identified 5 missense variants in SCN5A that had previously been associated with long QT syndrome (A572D, G615E), reported to alter sodium channel function (F2004L), or not previously reported in control populations (A572F, W1205C). Of the four variants without prior functional data, three variants were located in the I–II linker (A572D, A572F, and G615E), and all resulted in significantly shorter recovery times from inactivation. When compared to 733 control samples from the same population, the overall frequency of these rare variants in SCN5A was significantly higher in the SCD cases (6/60, 10.0%) as compared to controls (12/733, 1.6%); P=0.001.
Conclusion: Functionally significant mutations and rare variants in SCN5A may contribute to SCD risk among women.