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Eur Heart J. 2016 May 7;37(18):1456-64. doi: 10.1093/eurheartj/ehv695. Epub 2015 Dec 28.

The genetics underlying acquired long QT syndrome: impact for genetic screening.

Author information

1
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.
2
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.
3
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
4
IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.
5
AP-HP, Hôpital Bichat, Service de Cardiologie, Centre de Référence des Maladies Cardiaques Héréditaires, Université Denis Diderot, Paris 7, Paris, France.
6
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.
7
Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
8
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
9
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
10
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
11
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.
12
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
13
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.
14
Medical Statistics, Shiga University of Medical Science, Otsu, Shiga, Japan.
15
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
16
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.

Abstract

AIMS:

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.

METHODS AND RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

Acquired long QT syndrome; Congenital long QT syndrome; Drug-induced long QT syndrome; Genetics

PMID:
26715165
PMCID:
PMC4914885
DOI:
10.1093/eurheartj/ehv695
[Indexed for MEDLINE]
Free PMC Article

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