TY - JOUR
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 J.
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
PY - 2007
Y1 - 2007
N2 - BACKGROUND: Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded I(Ks) 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 ( <or = 50%) reduction in cardiac repolarizing I(Ks) 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 I(Ks) 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 ( <or = 50%) reduction in cardiac repolarizing I(Ks) 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
U2 - https://doi.org/10.1161/CIRCULATIONAHA.106.665406
DO - https://doi.org/10.1161/CIRCULATIONAHA.106.665406
M3 - Article
C2 - 17470695
SN - 0009-7322
VL - 115
SP - 2481
EP - 2489
JO - Circulation
JF - Circulation
IS - 19
ER -