title: The genetics underlying acquired long QT syndrome: impact for genetic screening.
abstract: Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors.
  
  
  
  We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations.
  
  
  
  A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan Inserm, UMR_S1166, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institut de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition, Paris, France Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Spazzolini
authors.affiliation: AP-HP, Hôpital Bichat, Service de Cardiologie, Centre de Référence des Maladies Cardiaques Héréditaires, Université Denis Diderot, Paris 7, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.affiliation: Inserm, UMR_S1166, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institut de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition, Paris, France Institute of Cardiometabolism and Nutrition (ICAN), Paris, France AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service de Biochimie Métabolique, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan Department of Pharmacology, Medical School of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Mastantuono
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Dagradi
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pedrazzini
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Inserm, UMR_S1166, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institut de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition, Paris, France Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Berthet
authors.affiliation: Medical Statistics, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.affiliation: Inserm, UMR_S1166, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institut de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition, Paris, France Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan horie@belle.shiga-med.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D004562:Electrocardiography; D005260:Female; D005602:France; D005820:Genetic Testing; D006801:Humans; D007558:Italy; D007564:Japan; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D009154:Mutation
keywords: Acquired long QT syndrome; Congenital long QT syndrome; Drug-induced long QT syndrome; Genetics