Cardiac channel molecular autopsy: Insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing

David J. Tester, Argelia Medeiros-Domingo, Melissa L. Will, Carla M. Haglund, Michael John Ackerman

Research output: Contribution to journalArticle

145 Citations (Scopus)

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 autopsynegative 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.

Original languageEnglish (US)
Pages (from-to)524-539
Number of pages16
JournalMayo Clinic Proceedings
Volume87
Issue number6
DOIs
StatePublished - 2012

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Genetic Testing
Sudden Death
Autopsy
Long QT Syndrome
Coroners and Medical Examiners
Mutation
DNA Sequence Analysis
Genes
Sleep
Genotype
High Pressure Liquid Chromatography
Exercise
Phenotype
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

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Cardiac channel molecular autopsy : Insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. / Tester, David J.; Medeiros-Domingo, Argelia; Will, Melissa L.; Haglund, Carla M.; Ackerman, Michael John.

In: Mayo Clinic Proceedings, Vol. 87, No. 6, 2012, p. 524-539.

Research output: Contribution to journalArticle

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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 autopsynegative 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.",
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