Original article
Cardiac Channel Molecular Autopsy: Insights From 173 Consecutive Cases of Autopsy-Negative Sudden Unexplained Death Referred for Postmortem Genetic Testing

https://doi.org/10.1016/j.mayocp.2012.02.017Get rights and content

Abstract

Objective

To perform long QT syndrome and catecholaminergic polymorphic ventricular tachycardia cardiac channel postmortem genetic testing (molecular autopsy) for a large cohort of cases of autopsy-negative sudden unexplained death (SUD).

Methods

From September 1, 1998, through October 31, 2010, 173 cases of SUD (106 males; mean ± SD age, 18.4±12.9 years; age range, 1-69 years; 89% white) were referred by medical examiners or coroners for a cardiac channel molecular autopsy. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, a comprehensive mutational analysis of the long QT syndrome susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) and a targeted analysis of the catecholaminergic polymorphic ventricular tachycardia type 1–associated gene (RYR2) were conducted.

Results

Overall, 45 putative pathogenic mutations absent in 400 to 700 controls were identified in 45 autopsy-negative SUD cases (26.0%). Females had a higher yield (26/67 [38.8%]) than males (19/106 [17.9%]; P<.005). Among SUD cases with exercise-induced death, the yield trended higher among the 1- to 10-year-olds (8/12 [66.7%]) compared with the 11- to 20-year-olds (4/27 [14.8%]; P=.002). In contrast, for those who died during a period of sleep, the 11- to 20-year-olds had a higher yield (9/25 [36.0%]) than the 1- to 10-year-olds (1/24 [4.2%]; P=.01).

Conclusion

Cardiac channel molecular autopsy should be considered in the evaluation of autopsy-negative SUD. Several interesting genotype-phenotype observations may provide insight into the expected yields of postmortem genetic testing for SUD and assist in selecting cases with the greatest potential for mutation discovery and directing genetic testing efforts.

Section snippets

Medical Examiner–Referred Cases of Autopsy-Negative SUD

From September 1, 1998, through October, 31, 2010, 173 medical examiners' cases of autopsy-negative SUD (106 males; mean ± SD age, 18.4±12.9 years; range, 1-69 years) were referred to Mayo Clinic's Windland Smith Rice Sudden Death Genomics Laboratory for a cardiac channel molecular autopsy. After receipt of written consent from the decedent's appropriate next of kin for this Mayo Foundation Institutional Review Board–approved protocol, a postmortem genetic mutational analysis (ie, cardiac

Cohort Description

Demographic characteristics for this consecutively referred SUD cohort are given in Table 1. Briefly, there were 173 cases (106 males and 67 females; mean ± SD age, 18.4±12.9 years; range, 1-69 years; 89% white). The mean ± SD ages of the males (18.2±13 years; range, 1-69 years) and females (18.8±13 years; range, 1-52 years) were similar. Most (161/173 [93.1%]) were 40 years or younger at their SUD. The circumstance (events or triggers) surrounding the SUD was grouped into 1 of 3 categories,

Discussion

Postmortem genetic testing (the cardiac channel molecular autopsy) has not yet been transformed fully from a research-based effort into a routine, standard part of the conventional autopsy when the coroner, medical examiner, or forensic pathologist is faced with a case of SUD in the young. However, recently, Basso and colleagues,18 on behalf of the Association for European Cardiovascular Pathology, have strongly recommended postmortem genetic analysis in both structural and nonstructural

Conclusion

More than one-fourth of autopsy-negative SUD cases may stem from either LQTS- or CPVT-associated channelopathic mutations. 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 girls, and those with a positive personal or family history of cardiac events. A 2-tiered approach starting with the LQTS-susceptibility genes for female patients with SUD and the CPVT

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    Grant Support: This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, the Sheikh Zayed Saif Mohammed Al Nahyan Fund in Pediatric Cardiology Research, the Dr. Scholl Fund, the Hannah M. Wernke Memorial Fund, and the National Institutes of Health, grant number HD42569.

    Potential Competing Interests: M.J.A. is a consultant for Biotronik, Boston Scientific, Medtronic, St. Jude Medical Inc, and Transgenomic. Intellectual property derived from M.J.A.'s research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals, recently acquired by Transgenomic). D.J.T., A.M.-D., M.L.W., and C.M.H. have no conflicts to disclose. M.J.A. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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