Will, Melissa L

Background: Potentially lethal syndromes such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a significant number of autopsy-negative sudden unexplained deaths (SUD). Here, the spectrum and prevalence of putative LQTS-/CPVT-causative mutations in autopsy- negative SUD was determined following a cardiac channel molecular autopsy. Methods: From September 1998 to October 2010, 173 cases of SUD (106 males, 18 ± 13 years, 89% white) were referred by Medical Examiners/Coroners for a cardiac channel molecular autopsy. Using PCR, DHPLC, and DNA sequencing, a comprehensive mutational analysis of the LQTS-susceptibility genes ( KCNQ1 , KCNH2 , SCN5A, KCNE1, and KCNE2 ) and a targeted analysis of the CPVT1-associated gene ( RYR2 ) was conducted. Results: Overall, 45 putative pathogenic mutations (20 RYR2 , 11 KCNQ1 , 6 KCNH2 , 6 SCN5A , and 2 KCNE2 , absent in 400 - 700 controls, were identified in 45 (26%) autopsy negative SUD cases. The yield was greatest for those with an exercise-induced death (16/46, 35%) or a positive personal/family history of a syncope (13/25, 52%), or sudden death (9/20, 45%). Females had a higher yield (26/67, 39%) than males (19/106, 18%, p < 0.005) especially if the SUD was during adolescence (12/25, 48% females vs. 9/50, 18% males). Females were more likely to have LQTS-associated mutations (65%) while males were more likely to have CPVT1-associated mutations (58%). Among SUD victims with exercise-induced death, the yield was much higher among the 1 - 10 year olds compared to the 11 -20 year olds (females, 71% vs 14%, p<0.05; males, 60% vs 15%, p = 0.07). However for those with death during a period of sleep, the 11 - 20 year olds had a much higher yield than the 1-10 year old group (females, 75% vs 0%, p<0.01; males 18% vs 6%). Conclusions: Over one-fourth of autopsy-negative SUD may stem from LQTS and CPVT. A cardiac channel molecular autopsy should be considered as a standard part of the evaluation of autopsy-negative SUD especially among children with exercise-induced SUD, adolescent females, and those with a positive personal/family history of cardiac events. A two-tiered approach starting with the LQTS-susceptibility genes in females and the CPVT-susceptibility genes in males may be prudent.