Postmortem molecular screening in unexplained sudden death

Sumeet S. Chugh, Olga Senashova, Allison Watts, Phuoc T. Tran, Zhengfeng Zhou, Qiuming Gong, Jack L. Titus, Susan J. Hayflick

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Objectives We examined the prevalence of defects in arrhythmia-related candidate genes among patients with unexplained sudden cardiac death (SCD). Background Patients with unexplained sudden death may constitute up to 5% of overall SCD cases. For such patients, systematic postmortem genetic analysis of archived tissue, using a candidate gene approach, may identify etiologies of SCD. Methods We performed analysis of KCNQ1 (KVLQT1), KCNH2 (HERG), SCN5A, KCNE1, and KCNE2 defects in a subgroup of 12 adult subjects with unexplained sudden death, derived from a 13-year, 270-patient autopsy series of SCD. Archived, paraffin-embedded myocardial tissue blocks obtained at the original postmortem examination were the source of deoxyribonucleic acid for genetic analysis. Results Two patients were found to have the same HERG defect, a missense mutation in exon 7 (nucleotide change G1681A, coding effect A561T). The mutation was heterozygous in Patient 1, but Patient 2 appeared to be homozygous for the defect. Patch-clamp recordings showed that the A561T mutant channel expressed in human embryonic kidney cells failed to generate HERG current. Western blot analysis implicated a trafficking defect in the protein, resulting in loss of post-translational processing from the immature to the mature form of HERG. No mutations were detected among the remaining four candidate genes. Conclusions In this autopsy series, only 2 of 12 patients with unexplained sudden death were observed to have a defect in HERG among five candidate genes tested. It is likely that elucidation of SCD mechanisms in such patients will await the discovery of multiple, novel arrhythmia-causing gene defects.

Original languageEnglish (US)
Pages (from-to)1625-1629
Number of pages5
JournalJournal of the American College of Cardiology
Volume43
Issue number9
DOIs
StatePublished - May 5 2004

Keywords

  • ECG
  • HEK
  • LQTS
  • PCR
  • SCD
  • SSCP
  • electrocardiogram
  • human embryonic kidney
  • long QT syndrome
  • polymerase chain reaction
  • single-stranded conformational polymorphism
  • sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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