Clinical research: electrophysiology
Postmortem molecular screening in unexplained sudden death

https://doi.org/10.1016/j.jacc.2003.11.052Get rights and content
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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 KCNE2defects 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 HERGdefect, 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 HERGcurrent. 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 HERGamong 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.

Abbreviations

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

Cited by (0)

This study was supported, in part, by a grant-in-aid from the American Heart Association to Dr. Chugh, who is also funded by the Association of Teachers of Preventive Medicine/CDC Cooperative Agreement (project TS-0660) and the Doris Duke Foundation Innovation in Clinical Research Award. Dr. Zhou is supported by grant HL68854 from the National Institutes of Health, Bethesda, Maryland, and the Howard Hughes Medical Institute Biomedical Research Support Program.