Whole-exome molecular autopsy after exertion-related sudden unexplained death in the young

Jason H. Anderson, David J. Tester, Melissa L. Will, Michael John Ackerman

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Background - Targeted postmortem genetic testing of the 4 major channelopathy-susceptibility genes (KCNQ1, KCNH2, SCN5A, and RYR2) have yielded putative pathogenic mutations in ≤30% of autopsy-negative sudden unexplained death in the young (SUDY) cases with highest yields derived from the subset of exertion-related SUDY. Here, we evaluate the role of whole-exome sequencing in exertion-related SUDY cases. Methods and Results - From 1998 to 2010, 32 cases of exertion-related SUDY were referred by Medical Examiners for a cardiac channel molecular autopsy. A mutational analysis of the major long-QT syndrome-susceptibility genes (KCNQ1, KCNH2, and SCN5A) and catecholaminergic polymorphic ventricular tachycardia-susceptibility gene (RYR2) identified a putative pathogenic mutation in 11 cases. Whole-exome sequencing was performed on the remaining 21 targeted gene-negative SUDY cases. After whole-exome sequencing, a gene-specific surveillance of all genes (N=100) implicated in sudden death was performed to identify putative pathogenic mutation(s). Three of these 21 decedents had a clinically actionable, pathogenic mutation (CALM2-F90L, CALM2-N98S, and PKP2-N634fs). Of the 18 remaining cases, 7 hosted at least 1 variant of unknown significance with a minor allele frequency

Original languageEnglish (US)
Pages (from-to)259-265
Number of pages7
JournalCirculation: Cardiovascular Genetics
Volume9
Issue number3
DOIs
StatePublished - Jun 1 2016

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Keywords

  • autopsy
  • exome
  • genetic testing
  • mutation
  • phenotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

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