Postmortem molecular screening in unexplained sudden death

• Published in: Journal of the American College of Cardiology Vol. 43; no. 9; pp. 1625 - 1629
• Main Authors: Chugh, Sumeet S, Senashova, Olga, Watts, Allison, Tran, Phuoc T, Zhou, Zhengfeng, Gong, Qiuming, Titus, Jack L, Hayflick, Susan J
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 05.05.2004; Elsevier Science; Elsevier Limited
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Automation; Biological and medical sciences; Bundle-Branch Block - genetics; Bundle-Branch Block - pathology; Cardiac arrhythmia; Cardiology; Cardiology. Vascular system; Cation Transport Proteins - genetics; Death, Sudden, Cardiac - etiology; Death, Sudden, Cardiac - pathology; Defects; Deoxyribonucleic acid; DNA; Electrocardiography; Emergency and intensive care: neonates and children. Prematurity. Sudden death; Ether-A-Go-Go Potassium Channels; Family medical history; Female; Genetic Predisposition to Disease - genetics; Genetic Testing; Heart; Humans; Intensive care medicine; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Long QT Syndrome - genetics; Long QT Syndrome - pathology; Male; Medical examiners; Medical sciences; Minnesota; Mutagenesis; Mutation; Mutation, Missense - genetics; Patients; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Potassium Channels - genetics; Potassium Channels, Voltage-Gated; Minnesota; United States > US; California; ECG; SSCP; SCD; PCR; LQTS; HEK; Cardiovascular disease; Medical screening; Heart disease; Sudden death; Postmortem
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2003.11.052

We examined the prevalence of defects in arrhythmia-related candidate genes among patients with unexplained sudden cardiac death (SCD). 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. 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. 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. 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.