Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds.
BACKGROUND
Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease.


OBJECTIVE
The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1-40 years old.


METHODS
Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1-40 years.


RESULTS
Over 26 months (2006-2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months-40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%-27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype-genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%-27%).


CONCLUSIONS
Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.
Greenlane Paediatric and Congenital Cardiac Services, Starship Childrens Hospital, Auckland, New Zealand. jskinner@adhb.govt.nz
Jonathan R
JR
Skinner
Jackie
J
Crawford
Warren
W
Smith
Andrew
A
Aitken
David
D
Heaven
Cary-Anne
CA
Evans
Ian
I
Hayes
Katherine R
KR
Neas
Simon
S
Stables
Timothy
T
Koelmeyer
Lloyd
L
Denmark
Jane
J
Vuletic
Fraser
F
Maxwell
Kate
K
White
Tao
T
Yang
Dan M
DM
Roden
Trond P
TP
Leren
Andrew
A
Shelling
Donald R
DR
Love
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D016757:Death, Sudden, Cardiac / Q000453:epidemiology*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009520:New Zealand / Q000453:epidemiology; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D011446:Prospective Studies; D016036:Seroepidemiologic Studies; D015222:Sodium Channels / Q000235:genetics*; D055815:Young Adult
D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels