Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene

Arthur J. Moss, Wataru Shimizu, Arthur A M Wilde, Jeffrey A. Towbin, Wojciech Zareba, Jennifer L. Robinson, Ming Qi, G. Michael Vincent, Michael John Ackerman, Elizabeth S. Kaufman, Nynke Hofman, Rahul Seth, Shiro Kamakura, Yoshihiro Miyamoto, Ilan Goldenberg, Mark L. Andrews, Scott McNitt

Research output: Contribution to journalArticle

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Abstract

BACKGROUND - Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. METHODS AND RESULTS - We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands' LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. CONCLUSIONS - This genotype-phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.

Original languageEnglish (US)
Pages (from-to)2481-2489
Number of pages9
JournalCirculation
Volume115
Issue number19
DOIs
StatePublished - May 2007

Fingerprint

Romano-Ward Syndrome
Mutation
Genes
Long QT Syndrome
Intermediate-Conductance Calcium-Activated Potassium Channels
Ion Channels
Registries
Haploinsufficiency
Hospital Distribution Systems
Phenotype
Proportional Hazards Models
Netherlands
Survival Rate
Genotype

Keywords

  • Electrocardiography
  • Genetics
  • Long-QT syndrome

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Moss, A. J., Shimizu, W., Wilde, A. A. M., Towbin, J. A., Zareba, W., Robinson, J. L., ... McNitt, S. (2007). Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation, 115(19), 2481-2489. https://doi.org/10.1161/CIRCULATIONAHA.106.665406

Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. / Moss, Arthur J.; Shimizu, Wataru; Wilde, Arthur A M; Towbin, Jeffrey A.; Zareba, Wojciech; Robinson, Jennifer L.; Qi, Ming; Vincent, G. Michael; Ackerman, Michael John; Kaufman, Elizabeth S.; Hofman, Nynke; Seth, Rahul; Kamakura, Shiro; Miyamoto, Yoshihiro; Goldenberg, Ilan; Andrews, Mark L.; McNitt, Scott.

In: Circulation, Vol. 115, No. 19, 05.2007, p. 2481-2489.

Research output: Contribution to journalArticle

Moss, AJ, Shimizu, W, Wilde, AAM, Towbin, JA, Zareba, W, Robinson, JL, Qi, M, Vincent, GM, Ackerman, MJ, Kaufman, ES, Hofman, N, Seth, R, Kamakura, S, Miyamoto, Y, Goldenberg, I, Andrews, ML & McNitt, S 2007, 'Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene', Circulation, vol. 115, no. 19, pp. 2481-2489. https://doi.org/10.1161/CIRCULATIONAHA.106.665406
Moss, Arthur J. ; Shimizu, Wataru ; Wilde, Arthur A M ; Towbin, Jeffrey A. ; Zareba, Wojciech ; Robinson, Jennifer L. ; Qi, Ming ; Vincent, G. Michael ; Ackerman, Michael John ; Kaufman, Elizabeth S. ; Hofman, Nynke ; Seth, Rahul ; Kamakura, Shiro ; Miyamoto, Yoshihiro ; Goldenberg, Ilan ; Andrews, Mark L. ; McNitt, Scott. / Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. In: Circulation. 2007 ; Vol. 115, No. 19. pp. 2481-2489.
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T1 - Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene

AU - Moss, Arthur J.

AU - Shimizu, Wataru

AU - Wilde, Arthur A M

AU - Towbin, Jeffrey A.

AU - Zareba, Wojciech

AU - Robinson, Jennifer L.

AU - Qi, Ming

AU - Vincent, G. Michael

AU - Ackerman, Michael John

AU - Kaufman, Elizabeth S.

AU - Hofman, Nynke

AU - Seth, Rahul

AU - Kamakura, Shiro

AU - Miyamoto, Yoshihiro

AU - Goldenberg, Ilan

AU - Andrews, Mark L.

AU - McNitt, Scott

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N2 - BACKGROUND - Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. METHODS AND RESULTS - We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands' LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. CONCLUSIONS - This genotype-phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.

AB - BACKGROUND - Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. METHODS AND RESULTS - We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands' LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. CONCLUSIONS - This genotype-phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.

KW - Electrocardiography

KW - Genetics

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