title: The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases.
abstract: BACKGROUND
  Sudden unexplained death account for one-third of all sudden natural deaths in the young (1-35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long-QT syndrome (LQTS) genes in the general population. We therefore wanted to investigate the prevalence of mutations in an unselected population of sudden unexplained deaths in a nationwide setting.
  
  
  METHODS
  DNA for genetic testing was available for 44 cases of sudden unexplained death in Denmark in the period 2000-2006 (equaling 33% of all cases of sudden unexplained death in the age group). KCNQ1, KCNH2, and SCN5A were sequenced and in vitro electrophysiological studies were performed on novel mutations.
  
  
  RESULTS
  In total, 5 of 44 cases (11%) carried a mutation in 1 of the 3 genes corresponding to 11% of all investigated cases (R190W KCNQ1, F29L KCNH2 (2 cases), P297S KCNH2 and P1177L SCN5A). P1177L SCN5A has not been reported before. In vitro electrophysiological studies of P1177L SCN5A revealed an increased sustained current suggesting a LQTS phenotype.
  
  
  CONCLUSIONS
  In a nationwide setting, the genetic investigation of an unselected population of sudden unexplained death cases aged 1-35 years finds a lower than expected number of mutations compared to referred populations previously reported. We therefore conclude that the prevalence of mutations in the 3 major LQTS associated genes may not be as abundant as previously estimated.
authors.affiliation: Department of Cardiology, Rigshospitalet and Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Copenhagen, Denmark. bowinkel@dadlnet.dk
authors.forename: Bo Gregers
authors.initials: BG
authors.lastname: Winkel
authors.forename: Maiken Kudahl
authors.initials: MK
authors.lastname: Larsen
authors.forename: Knut Erik
authors.initials: KE
authors.lastname: Berge
authors.forename: Trond Paul
authors.initials: TP
authors.lastname: Leren
authors.forename: Peter Henrik
authors.initials: PH
authors.lastname: Nissen
authors.forename: Morten Salling
authors.initials: MS
authors.lastname: Olesen
authors.forename: Mads Vilhelm
authors.initials: MV
authors.lastname: Hollegaard
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Nielsen
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.forename: Jesper Hastrup
authors.initials: JH
authors.lastname: Svendsen
authors.forename: Yinman
authors.initials: Y
authors.lastname: Wang
authors.forename: Ingrid Bayer
authors.initials: IB
authors.lastname: Kristensen
authors.forename: Henrik Kjaerulf
authors.initials: HK
authors.lastname: Jensen
authors.forename: Jacob
authors.initials: J
authors.lastname: Tfelt-Hansen
authors.forename: Jytte
authors.initials: J
authors.lastname: Banner
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D001344:Autopsy; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000453:epidemiology / Q000209:etiology*; D003718:Denmark; D000072237:ERG1 Potassium Channel; D022062:Electrophysiologic Techniques, Cardiac; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008564:Membrane Potentials; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D029597:Romano-Ward Syndrome / Q000235:genetics / Q000401:mortality; D014162:Transfection; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human