Spectrum of mutations in Long-QT Syndrome genes

KVLQT1, HERG, SCN5A, KCNE1, and KCNE2

Igor Splawski, Jiaxiang Shen, Katherine W. Timothy, Michael H. Lehmann, Silvia Priori, Jennifer L. Robinson, Arthur J. Moss, Peter J. Schwartz, Jeffrey Towbin, G. Michael Vincent, Mark T. Keating

Research output: Contribution to journalArticle

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Abstract

Background - Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Methods and Results - We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals). Conclusions - KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.

Original languageEnglish (US)
Pages (from-to)1178-1185
Number of pages8
JournalCirculation
Volume102
Issue number10
DOIs
StatePublished - Sep 5 2000
Externally publishedYes

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Long QT Syndrome
Mutation
Genes
Jervell-Lange Nielsen Syndrome
Romano-Ward Syndrome
RNA Splice Sites
Frameshift Mutation
Syncope
Deafness
Missense Mutation
Sudden Death
Electrocardiography
Seizures

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., ... Keating, M. T. (2000). Spectrum of mutations in Long-QT Syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation, 102(10), 1178-1185. https://doi.org/10.1161/01.CIR.102.10.1178

Spectrum of mutations in Long-QT Syndrome genes : KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. / Splawski, Igor; Shen, Jiaxiang; Timothy, Katherine W.; Lehmann, Michael H.; Priori, Silvia; Robinson, Jennifer L.; Moss, Arthur J.; Schwartz, Peter J.; Towbin, Jeffrey; Vincent, G. Michael; Keating, Mark T.

In: Circulation, Vol. 102, No. 10, 05.09.2000, p. 1178-1185.

Research output: Contribution to journalArticle

Splawski, I, Shen, J, Timothy, KW, Lehmann, MH, Priori, S, Robinson, JL, Moss, AJ, Schwartz, PJ, Towbin, J, Vincent, GM & Keating, MT 2000, 'Spectrum of mutations in Long-QT Syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2', Circulation, vol. 102, no. 10, pp. 1178-1185. https://doi.org/10.1161/01.CIR.102.10.1178
Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL et al. Spectrum of mutations in Long-QT Syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-1185. https://doi.org/10.1161/01.CIR.102.10.1178
Splawski, Igor ; Shen, Jiaxiang ; Timothy, Katherine W. ; Lehmann, Michael H. ; Priori, Silvia ; Robinson, Jennifer L. ; Moss, Arthur J. ; Schwartz, Peter J. ; Towbin, Jeffrey ; Vincent, G. Michael ; Keating, Mark T. / Spectrum of mutations in Long-QT Syndrome genes : KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. In: Circulation. 2000 ; Vol. 102, No. 10. pp. 1178-1185.
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abstract = "Background - Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Methods and Results - We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68{\%} of individuals). Conclusions - KVLQT1 (42{\%}) and HERG (45{\%}) accounted for 87{\%} of identified mutations, and SCN5A (8{\%}), KCNE1 (3{\%}), and KCNE2 (2{\%}) accounted for the other 13{\%}. Missense mutations were most common (72{\%}), followed by frameshift mutations (10{\%}), in-frame deletions, and nonsense and splice-site mutations (5{\%} to 7{\%} each). Most mutations resided in intracellular (52{\%}) and transmembrane (30{\%}) domains; 12{\%} were found in pore and 6{\%} in extracellular segments. In most cases (78{\%}), a mutation was found in a single family or an individual.",
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T1 - Spectrum of mutations in Long-QT Syndrome genes

T2 - KVLQT1, HERG, SCN5A, KCNE1, and KCNE2

AU - Splawski, Igor

AU - Shen, Jiaxiang

AU - Timothy, Katherine W.

AU - Lehmann, Michael H.

AU - Priori, Silvia

AU - Robinson, Jennifer L.

AU - Moss, Arthur J.

AU - Schwartz, Peter J.

AU - Towbin, Jeffrey

AU - Vincent, G. Michael

AU - Keating, Mark T.

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N2 - Background - Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Methods and Results - We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals). Conclusions - KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.

AB - Background - Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Methods and Results - We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals). Conclusions - KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.

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