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

Christiansen, Michael ; Hedley, Paula L. ; Theilade, Juliane ; Stoevring, Birgitte ; Leren, Trond P. ; Eschen, Ole ; Sørensen, Karina M. ; Tybjærg-Hansen, Anne ; Ousager, Lilian B. ; Pedersen, Lisbeth N. ; Frikke-Schmidt, Ruth ; Aidt, Frederik H. ; Hansen, Michael G. ; Hansen, Jim ; Bloch Thomsen, Poul E. ; Toft, Egon ; Henriksen, Finn L. ; Bundgaard, Henning ; Jensen, Henrik K. ; Kanters, Jorgen K. (2014-03)

Please cite as follows: Christiansen, M. et al. 2014. Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. BMC Medical Genetics, 15(1):31, doi:10.1186/1471-2350-15-31.

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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&#8201;&gt;&#8201;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 &#8220;unrelated&#8221; 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.

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