Targeted Mutational Analysis of the RyR2-Encoded Cardiac Ryanodine Receptor in Sudden Unexplained Death: A Molecular Autopsy of 49 Medical Examiner/Coroner's Cases

Tester, David J.; Spoon, Daniel B.; Valdiva, Hector H.; Makielski, Jonathan C.; Ackerman, Michael J.
November 2004
Mayo Clinic Proceedings;Nov2004, Vol. 79 Issue 11, p1380
Academic Journal
OBJECTIVE: To perform a molecular autopsy of the RyR2-encoded cardiac ryanodine receptor/calcium release channel In medical examiner/coroner's cases of sudden unexplained death (SUD). METHODS: From September 1998 to March 2004, 49 cases of SUD were referred by medical examiners/coroners to the Sudden Death Genomics Laboratory at the Mayo Clinic In Rochester, Minn, for a cardiac channel molecular autopsy. Mutational analysis of LB exons of RyR2 implicated previously in the pathogenesis of catechoiaminergic polymorphic ventricular tachycardia (CPVT) was performed on genomic DNA using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing. RESULTS: This cohort of 49 cases of SW) included 30 males, 13 with a family history of syncope, cardiac arrest, or sudden cardiac death (mean ± SD age at death, 14.2&plusm;10.9 years). Six distinct RyR2 missense mutations (3 novel) were discovered In 7 cases (14%, 6 males, mean ± SD age at death, 13.6±11.2 years) of SUD. The activities at the time of SUD were exertion (3), emotion (1), and unknown (3). The mutations, R420W, S2246L, N4097S, E4146K, T4158P, and R4491C, involved nonconservative amino acid substitutions in highly conserved residues across species and were not seen In 400 reference alleles. CONCLUSIONS: This study represents the first molecular autopsy of RyR2 In medical examiner-referred cases of SUD. A targeted analysis of only 18 of the 105 protein-encoding exons of the cardiac ryanodine receptor/calcium release channel revealed potential CPVTI-causing RyR2 mutations in 1 of every 7 cases of SUD. These findings suggest that postmortem genetic testing of RyR2 should be considered as a part of the comprehensive medicolegal autopsy investigation of a SUD case and that this potentially heritable and often elusive arrhythmia syndrome be scrutinized carefully in family members of those who experience SUD.


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