The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds:: Toward a mutation-specific risk stratification

被引:127
作者
Crotti, Lia
Spazzolini, Carla
Schwartz, Peter J. [1 ]
Shimizu, Wataru
Denjoy, Isabelle
Schulze-Bahr, Eric
Zaklyazminskaya, Elena V.
Swan, Heikki
Ackerman, Michael J.
Moss, Arthur J.
Wilde, Arthur A. M.
Horie, Minoru
Brink, Paul A.
Insolia, Roberto
De Ferrari, Gaetano M.
Crimi, Gabriele
机构
[1] IRCCS, Fdn Policlin San Matteo, Dept Cardiol, Mol Cardiol Lab, I-1927100 Pavia, Italy
[2] Univ Stellenbosch, Dept Med, ZA-7600 Stellenbosch, South Africa
[3] IRCCS, Inst Auxolog, Lab Cardiovasc Genet, Milan, Italy
[4] Univ Cape Town, Hatter Inst Cardiovasc Res, Dept Med, Cardiovasc Genet Lab, ZA-7925 Cape Town, South Africa
[5] Natl Cardiovasc Ctr, Dept Internal Med, Div Cardiol, Osaka, Japan
[6] Hop Lariboisiere, INSERM, Serv Cardiol, U582, Paris, France
[7] Univ Munich, Med Klin & Poliklin C, Mol Genet & Spezialambulanz Patienten Angeborenen, Munster, Germany
[8] Med Genet Res Ctr, Lab DNA Res, Moscow, Russia
[9] Helsinki Univ Hosp, Dept Cardiol, Helsinki, Finland
[10] Coll Med, Mayo Clin, Dept Med, Rochester, MN USA
[11] Coll Med, Mayo Clin, Dept Pediat, Rochester, MN USA
[12] Coll Med, Mayo Clin, Dept Mol Pharmacol, Rochester, MN USA
[13] Coll Med, Mayo Clin, Dept Expt Therapeut, Rochester, MN USA
[14] Coll Med, Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA
[15] Coll Med, Mayo Clin, Div Pediat Cardiol, Rochester, MN USA
[16] Univ Rochester, Med Ctr, Dept Med, Div Cardiol, Rochester, NY 14642 USA
[17] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands
[18] Shiga Univ Med Sci, Dept Cardiol, Otsu, Shiga, Japan
关键词
arrhythmia; death; sudden; genetics; long-QT syndrome; risk factors;
D O I
10.1161/CIRCULATIONAHA.107.726950
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background - The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)-causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families. Methods and Results - Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484 +/- 42 versus 485 +/- 45 ms (P=NS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485 +/- 43 versus 465 +/- 38 ms) (all P < 0.001). Arrhythmic risk remained higher (P < 0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite beta-blocker therapy. Conclusions - The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.
引用
收藏
页码:2366 / 2375
页数:10
相关论文
共 24 条
[1]   RESTRICTION SITES CONTAINING CPG SHOW A HIGHER FREQUENCY OF POLYMORPHISM IN HUMAN DNA [J].
BARKER, D ;
SCHAFER, M ;
WHITE, R .
CELL, 1984, 36 (01) :131-138
[2]   Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population [J].
Brink, PA ;
Crotti, L ;
Corfield, V ;
Goosen, A ;
Durrheim, G ;
Hedley, P ;
Heradien, M ;
Geldenhuys, G ;
Vanoli, E ;
Bacchini, S ;
Spazzolini, C ;
Lundquist, AL ;
Roden, DM ;
George, AL ;
Schwartz, PJ .
CIRCULATION, 2005, 112 (17) :2602-2610
[3]   KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome [J].
Donger, C ;
Denjoy, I ;
Berthet, M ;
Neyroud, N ;
Cruaud, C ;
Bennaceur, M ;
Chivoret, G ;
Schwartz, K ;
Coumel, P ;
Guicheney, P .
CIRCULATION, 1997, 96 (09) :2778-2781
[4]   Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome [J].
Kobori, A ;
Sarai, N ;
Shimizu, W ;
Nakamura, Y ;
Murakami, Y ;
Makiyama, T ;
Ohno, S ;
Takenaka, K ;
Ninomiya, T ;
Fujiwara, Y ;
Matsuoka, S ;
Takano, M ;
Noma, A ;
Kita, T ;
Horie, M .
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, 2004, 15 (02) :190-199
[5]   25th anniversary of the international long-QT syndrome registry - An ongoing quest to uncover the secrets of long-QT syndrome [J].
Moss, AJ ;
Schwartz, PJ .
CIRCULATION, 2005, 111 (09) :1199-1201
[6]   Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel [J].
Moss, AJ ;
Zareba, W ;
Kaufman, ES ;
Gartman, E ;
Peterson, DR ;
Benhorin, J ;
Towbin, JA ;
Keating, MT ;
Priori, SG ;
Schwartz, PJ ;
Vincent, GM ;
Robinson, JL ;
Andrews, ML ;
Feng, CY ;
Hall, WJ ;
Medina, A ;
Zhang, L ;
Wang, ZQ .
CIRCULATION, 2002, 105 (07) :794-799
[7]   Effectiveness and limitations of β-blocker therapy in congenital long-QT syndrome [J].
Moss, AJ ;
Zareba, W ;
Hall, WJ ;
Schwartz, PJ ;
Crampton, RS ;
Benhorin, J ;
Vincent, GM ;
Locati, EH ;
Priori, SG ;
Napolitano, C ;
Medina, A ;
Zhang, L ;
Robinson, JL ;
Timothy, K ;
Towbin, JA ;
Andrews, ML .
CIRCULATION, 2000, 101 (06) :616-623
[8]   Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene [J].
Moss, Arthur J. ;
Shimizu, Wataru ;
Wilde, Arthur A. M. ;
Towbin, Jeffrey A. ;
Zareba, Wojciech ;
Robinson, Jennifer L. ;
Qi, Ming ;
Vincent, G. Michael ;
Ackerman, Michael J. ;
Kaufman, Elizabeth S. ;
Hofman, Nynke ;
Seth, Rahul ;
Kamakura, Shiro ;
Miyamoto, Yoshihiro ;
Goldenberg, Ilan ;
Andrews, Mark L. ;
McNitt, Scott .
CIRCULATION, 2007, 115 (19) :2481-2489
[9]   A founder mutation of the potassium channel KCNQ1 in long QT syndrome - Implications for estimation of disease prevalence and molecular diagnostics [J].
Piippo, K ;
Swan, H ;
Pasternack, M ;
Chapman, H ;
Paavonen, K ;
Viitasalo, M ;
Toivonen, L ;
Kontula, K .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2001, 37 (02) :562-568
[10]   Association of long QT syndrome loci and cardiac events among patients treated with β-blockers [J].
Priori, SG ;
Napolitano, C ;
Schwartz, PJ ;
Grillo, M ;
Bloise, R ;
Ronchetti, E ;
Moncalvo, C ;
Tulipani, C ;
Veia, A ;
Bottelli, G ;
Nastoli, J .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2004, 292 (11) :1341-1344