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J Am Coll Cardiol, 2007; 49:240-246, doi:10.1016/j.jacc.2006.10.010 (Published online 28 December 2006). © 2007 by the American College of Cardiology Foundation

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CLINICAL RESEARCH: HEART RHYTHM DISORDER

Postmortem Long QT Syndrome Genetic Testing for Sudden Unexplained Death in the Young

David J. Tester, BS^_* and Michael J. Ackerman, MD, PhD^_*,,,1,_*

^_* Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota.
Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota.
Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Manuscript received March 8, 2006; revised manuscript received April 12, 2006, accepted May 1, 2006.

^_* Reprint requests and correspondence: Dr. Michael J. Ackerman, Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905-0001. (Email: ackerman.michael{at}mayo.edu).

OBJECTIVES: This study sought to determine the spectrum and prevalence of long QT syndrome (LQTS)-associated mutations in a large cohort of autopsy-negative sudden unexplained death (SUD).

BACKGROUND: Potentially heritable arrhythmia syndromes may explain a significant proportion of SUD in the young. Here, comprehensive postmortem LQTS genetic testing was performed in a cohort of SUD cases.

METHODS: From September 1998 to March 2004, 49 cases of SUD (30 male patients, average age at death 14.2 ± 10.9 years) were referred by medical examiners/coroners to Mayo Clinic’s Sudden Death Genomics Laboratory. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, open reading frame/splice site mutational analysis was conducted for all 8 genes implicated in the pathogenesis of either LQTS (LQT1 to LQT6) or multisystem disorders involving either QT or QU prolongation.

RESULTS: Ten LQTS-associated mutations (4 novel) were discovered in 10 SUD cases (20%, 8 female patients, average age at death 18.0 ± 11.8 years). The LQTS susceptibility mutations LQT1 (5), LQT2 (3), and LQT3 (2) were far more common among women (8 of 18, 44%) than men (2 of 30, 6.7%, p < 0.008). The activities at the time of SUD included sleep (5), exertion (2), auditory arousal (1), and undetermined (2). Sudden death was the sentinel event in two-thirds of the cases.

CONCLUSIONS: In this cardiac channel-focused molecular autopsy investigation of SUD, over one-third of decedents harbored a putative cardiac channel mutation: 7 previously reported to host mutations in the RyR2-encoded calcium release channel and now 10 with LQTS susceptibility mutations. Accordingly, postmortem cardiac channel genetic testing should be pursued in the evaluation of autopsy-negative SUD.

Abbreviations and Acronyms   CPVT = catecholaminergic polymorphic ventricular tachycardia   ECG = electrocardiogram   LQTS = long QT syndrome   SCD = sudden cardiac death   SIDS = sudden infant death syndrome   SUD = sudden unexplained death

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