Postmortem molecular screening in unexplained sudden death.
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.
Chugh
Sumeet S
SS
Division of Cardiology, Oregon Health and Science University, Portland, 97239, USA. chughs@ohsu.edu
Senashova
Olga
O
Watts
Allison
A
Tran
Phuoc T
PT
Zhou
Zhengfeng
Z
Gong
Qiuming
Q
Titus
Jack L
JL
Hayflick
Susan J
SJ
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
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