title: Postmortem molecular screening in unexplained sudden death.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Cardiology, Oregon Health and Science University, Portland, 97239, USA. chughs@ohsu.edu
authors.forename: Sumeet S
authors.initials: SS
authors.lastname: Chugh
authors.forename: Olga
authors.initials: O
authors.lastname: Senashova
authors.forename: Allison
authors.initials: A
authors.lastname: Watts
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Gong
authors.forename: Jack L
authors.initials: JL
authors.lastname: Titus
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
mesh_terms: D000328:Adult; D002037:Bundle-Branch Block / Q000235:genetics / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000209:etiology* / Q000473:pathology*; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics / Q000473:pathology; D008297:Male; D008910:Minnesota; D020125:Mutation, Missense / Q000235:genetics; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated
chemical_list: D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated