CLINICAL RESEARCH: ELECTROPHYSIOLOGY
Postmortem molecular screening in unexplained sudden death
Sumeet S. Chugh, MD*,*,
Olga Senashova, BS*,
Allison Watts, MS*,
Phuoc T. Tran, MD, PhD ,
Zhengfeng Zhou, MD, PhD ,
Qiuming Gong, MD, PhD,
Jack L. Titus, MD, PhD and
Susan J. Hayflick, MD
* Division of Cardiology, Portland, OregonUSA
Division of Molecular Medicine, Portland, OregonUSA
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
Jesse E. Edwards Registry of Cardiovascular Disease, St. Paul, Minnesota, USA
Manuscript received October 8, 2003;
accepted November 6, 2003.
* Reprint requests and correspondence: Dr. Sumeet S. Chugh, Cardiology Division, UHN-62, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, USA.
chughs{at}ohsu.edu
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.
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Abbreviations and Acronyms
| | ECG | = electrocardiogram | | HEK | = human embryonic kidney | | LQTS | = long QT syndrome | | PCR | = polymerase chain reaction | | SCD | = sudden cardiac death | | SSCP | = single-stranded conformational polymorphism |
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