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 E Bloch Thomsen; Egon Toft; Finn L Henriksen; Henning Bundgaard; Henrik K Jensen; Jørgen K. Kanters

doi:10.1186/1471-2350-15-31

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 E Bloch Thomsen, Egon Toft, Finn L Henriksen, Henning Bundgaard, Henrik K Jensen, Jørgen K. Kanters

9 Citationer (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.

Originalsprog	Engelsk
Artikelnummer	31
Tidsskrift	BMC Medical Genetics
Vol/bind	15
Antal sider	11
ISSN	1471-2350
DOI	https://doi.org/10.1186/1471-2350-15-31
Status	Udgivet - 7 mar. 2014

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10.1186/1471-2350-15-31

Citationsformater

Christiansen, M., Hedley, P. L., Theilade, J., Stoevring, B., Leren, T. P., Eschen, O., Sørensen, K. M., Tybjærg-Hansen, A., Ousager, L. B., Pedersen, L. N., Frikke-Schmidt, R., Aidt, F. H., Hansen, M. G., Hansen, J., Bloch Thomsen, P. E., Toft, E., Henriksen, F. L., Bundgaard, H., Jensen, H. K., & Kanters, J. K. (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, [31]. https://doi.org/10.1186/1471-2350-15-31

Christiansen, M, Hedley, PL, Theilade, J, Stoevring, B, Leren, TP, Eschen, O, Sørensen, KM, Tybjærg-Hansen, A, Ousager, LB, Pedersen, LN, Frikke-Schmidt, R, Aidt, FH, Hansen, MG, Hansen, J, Bloch Thomsen, PE, Toft, E, Henriksen, FL, Bundgaard, H, Jensen, HK & Kanters, JK 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, bind 15, 31. https://doi.org/10.1186/1471-2350-15-31

@article{2c66832eb7994fe59b66bbaee25e62b0,

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.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.",

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",

author = "Michael Christiansen and Hedley, {Paula L.} and Juliane Theilade and Birgitte Stoevring and Leren, {Trond P.} and Ole Eschen and S{\o}rensen, {Karina M.} and Anne Tybj{\ae}rg-Hansen and Ousager, {Lilian B.} and Pedersen, {Lisbeth N.} and Ruth Frikke-Schmidt and Aidt, {Frederik H.} and Hansen, {Michael G} and Jim Hansen and {Bloch Thomsen}, {Poul E} and Egon Toft and Henriksen, {Finn L} and Henning Bundgaard and Jensen, {Henrik K} and Kanters, {J{\o}rgen K.}",

year = "2014",

month = mar,

day = "7",

doi = "10.1186/1471-2350-15-31",

language = "English",

volume = "15",

journal = "B M C Medical Genetics",

issn = "1471-2350",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2

AU - Christiansen, Michael

AU - Hedley, Paula L.

AU - Theilade, Juliane

AU - Stoevring, Birgitte

AU - Leren, Trond P.

AU - Eschen, Ole

AU - Sørensen, Karina M.

AU - Tybjærg-Hansen, Anne

AU - Ousager, Lilian B.

AU - Pedersen, Lisbeth N.

AU - Frikke-Schmidt, Ruth

AU - Aidt, Frederik H.

AU - Hansen, Michael G

AU - Hansen, Jim

AU - Bloch Thomsen, Poul E

AU - Toft, Egon

AU - Henriksen, Finn L

AU - Bundgaard, Henning

AU - Jensen, Henrik K

AU - Kanters, Jørgen K.

PY - 2014/3/7

Y1 - 2014/3/7

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - DNA Mutational Analysis

KW - Denmark

KW - Ether-A-Go-Go Potassium Channels

KW - Female

KW - Founder Effect

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Humans

KW - KCNQ1 Potassium Channel

KW - Long QT Syndrome

KW - Male

KW - Microsatellite Repeats

KW - Mutation, Missense

KW - NAV1.5 Voltage-Gated Sodium Channel

KW - Potassium Channels, Voltage-Gated

U2 - 10.1186/1471-2350-15-31

DO - 10.1186/1471-2350-15-31

M3 - Journal article

C2 - 24606995

SN - 1471-2350

VL - 15

JO - B M C Medical Genetics

JF - B M C Medical Genetics

M1 - 31

ER -

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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