title: Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2.
abstract: BACKGROUND
  Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A.
  
  
  METHODS
  We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2.
  
  
  RESULTS
  Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 "unrelated" families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000.
  
  
  CONCLUSIONS
  The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.
authors.affiliation: Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Ørestads Boulevard 5, 2300S, Copenhagen, Denmark. mic@ssi.dk.
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hedley
authors.forename: Juliane
authors.initials: J
authors.lastname: Theilade
authors.forename: Birgitte
authors.initials: B
authors.lastname: Stoevring
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
authors.forename: Ole
authors.initials: O
authors.lastname: Eschen
authors.forename: Karina M
authors.initials: KM
authors.lastname: Sørensen
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
authors.forename: Lilian B
authors.initials: LB
authors.lastname: Ousager
authors.forename: Lisbeth N
authors.initials: LN
authors.lastname: Pedersen
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.forename: Frederik H
authors.initials: FH
authors.lastname: Aidt
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hansen
authors.forename: Jim
authors.initials: J
authors.lastname: Hansen
authors.forename: Poul E
authors.initials: PE
authors.lastname: Bloch Thomsen
authors.forename: Egon
authors.initials: E
authors.lastname: Toft
authors.forename: Finn L
authors.initials: FL
authors.lastname: Henriksen
authors.forename: Henning
authors.initials: H
authors.lastname: Bundgaard
authors.forename: Henrik K
authors.initials: HK
authors.lastname: Jensen
authors.forename: Jørgen K
authors.initials: JK
authors.lastname: Kanters
mesh_terms: D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D003718:Denmark; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human