Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2

Michael Christiansen, Paula L Hedley, Juliane Theilade, Birgitte Stoevring, Trond P Leren, Ole Eschen, Karina M Sørensen, Anne Tybjærg-Hansen, Lilian B Ousager, Lisbeth N Pedersen, Ruth Frikke-Schmidt, Frederik H Aidt, Michael G Hansen, Jim Hansen, Poul Erik Bloch Thomsen, Egon Toft, Finn L Henriksen, Henning Bundgaard, Henrik K Jensen, Jørgen K Kanters

11 Citations (Scopus)

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.

CONCLUSION: 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.

Original languageEnglish
JournalB M C Medical Genetics
Volume15
Pages (from-to)31
ISSN1471-2350
DOIs
Publication statusPublished - 2014

Keywords

  • Case-Control Studies
  • DNA Mutational Analysis
  • Denmark
  • Ether-A-Go-Go Potassium Channels
  • Female
  • Founder Effect
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • KCNQ1 Potassium Channel
  • Long QT Syndrome
  • Male
  • Microsatellite Repeats
  • Mutation, Missense
  • NAV1.5 Voltage-Gated Sodium Channel
  • Potassium Channels, Voltage-Gated

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