TY - JOUR
T1 - Postmortem molecular screening in unexplained sudden death
AU - Chugh, Sumeet S.
AU - Senashova, Olga
AU - Watts, Allison
AU - Tran, Phuoc T.
AU - Zhou, Zhengfeng
AU - Gong, Qiuming
AU - Titus, Jack L.
AU - Hayflick, Susan J.
N1 - Funding Information:
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.
PY - 2004/5/5
Y1 - 2004/5/5
N2 - 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.
AB - 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.
KW - ECG
KW - HEK
KW - LQTS
KW - PCR
KW - SCD
KW - SSCP
KW - electrocardiogram
KW - human embryonic kidney
KW - long QT syndrome
KW - polymerase chain reaction
KW - single-stranded conformational polymorphism
KW - sudden cardiac death
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U2 - 10.1016/j.jacc.2003.11.052
DO - 10.1016/j.jacc.2003.11.052
M3 - Article
C2 - 15120823
AN - SCOPUS:2342440911
SN - 0735-1097
VL - 43
SP - 1625
EP - 1629
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 9
ER -