Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds

Background Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease. Objective The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1–40 years old. Methods Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1–40 years. Results Over 26 months (2006–2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months–40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%–27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype–genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%–27%). Conclusion Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.