BMC medical genetics · 2014
Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2.
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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 Jørgen K
Аннотация
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.
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.
Предметные рубрики MeSH
Case-Control StudiesDNA Mutational AnalysisDenmarkERG1 Potassium ChannelEther-A-Go-Go Potassium ChannelsFemaleFounder EffectGenetic Association StudiesGenetic Predisposition to DiseaseHaplotypesHumansKCNQ1 Potassium ChannelLong QT SyndromeMaleMicrosatellite RepeatsMutation, MissenseNAV1.5 Voltage-Gated Sodium ChannelPotassium Channels, Voltage-Gated