The genetics underlying acquired long QT syndrome: Impact for genetic screening

Hideki Itoh, Lia Crotti, Takeshi Aiba, Carla Spazzolini, Isabelle Denjoy, Veronique Fressart, Kenshi Hayashi, Tadashi Nakajima, Seiko Ohno, Takeru Makiyama, Jie Wu, Kanae Hasegawa, Elisa Mastantuono, Federica Dagradi, Matteo Pedrazzini, Masakazu Yamagishi, Myriam Berthet, Yoshitaka Murakami, Wataru Shimizu, Pascale GuicheneyPeter J. Schwartz, Minoru Horie

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1456-1464
Number of pages9
JournalEuropean Heart Journal
Volume37
Issue number18
DOIs
Publication statusPublished - May 7 2016

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Long QT Syndrome
Genetic Testing
Mutation
Torsades de Pointes
Inborn Genetic Diseases
Hypokalemia
Bradycardia
Ventricular Tachycardia

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

The genetics underlying acquired long QT syndrome : Impact for genetic screening. / Itoh, Hideki; Crotti, Lia; Aiba, Takeshi; Spazzolini, Carla; Denjoy, Isabelle; Fressart, Veronique; Hayashi, Kenshi; Nakajima, Tadashi; Ohno, Seiko; Makiyama, Takeru; Wu, Jie; Hasegawa, Kanae; Mastantuono, Elisa; Dagradi, Federica; Pedrazzini, Matteo; Yamagishi, Masakazu; Berthet, Myriam; Murakami, Yoshitaka; Shimizu, Wataru; Guicheney, Pascale; Schwartz, Peter J.; Horie, Minoru.

In: European Heart Journal, Vol. 37, No. 18, 07.05.2016, p. 1456-1464.

Research output: Contribution to journalArticle

Itoh, H, Crotti, L, Aiba, T, Spazzolini, C, Denjoy, I, Fressart, V, Hayashi, K, Nakajima, T, Ohno, S, Makiyama, T, Wu, J, Hasegawa, K, Mastantuono, E, Dagradi, F, Pedrazzini, M, Yamagishi, M, Berthet, M, Murakami, Y, Shimizu, W, Guicheney, P, Schwartz, PJ & Horie, M 2016, 'The genetics underlying acquired long QT syndrome: Impact for genetic screening', European Heart Journal, vol. 37, no. 18, pp. 1456-1464. https://doi.org/10.1093/eurheartj/ehv695
Itoh, Hideki ; Crotti, Lia ; Aiba, Takeshi ; Spazzolini, Carla ; Denjoy, Isabelle ; Fressart, Veronique ; Hayashi, Kenshi ; Nakajima, Tadashi ; Ohno, Seiko ; Makiyama, Takeru ; Wu, Jie ; Hasegawa, Kanae ; Mastantuono, Elisa ; Dagradi, Federica ; Pedrazzini, Matteo ; Yamagishi, Masakazu ; Berthet, Myriam ; Murakami, Yoshitaka ; Shimizu, Wataru ; Guicheney, Pascale ; Schwartz, Peter J. ; Horie, Minoru. / The genetics underlying acquired long QT syndrome : Impact for genetic screening. In: European Heart Journal. 2016 ; Vol. 37, No. 18. pp. 1456-1464.
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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.",
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T1 - The genetics underlying acquired long QT syndrome

T2 - Impact for genetic screening

AU - Itoh, Hideki

AU - Crotti, Lia

AU - Aiba, Takeshi

AU - Spazzolini, Carla

AU - Denjoy, Isabelle

AU - Fressart, Veronique

AU - Hayashi, Kenshi

AU - Nakajima, Tadashi

AU - Ohno, Seiko

AU - Makiyama, Takeru

AU - Wu, Jie

AU - Hasegawa, Kanae

AU - Mastantuono, Elisa

AU - Dagradi, Federica

AU - Pedrazzini, Matteo

AU - Yamagishi, Masakazu

AU - Berthet, Myriam

AU - Murakami, Yoshitaka

AU - Shimizu, Wataru

AU - Guicheney, Pascale

AU - Schwartz, Peter J.

AU - Horie, Minoru

PY - 2016/5/7

Y1 - 2016/5/7

N2 - 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.

AB - 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.

KW - Acquired long QT syndrome

KW - Congenital long QT syndrome

KW - Drug-induced long QT syndrome

KW - Genetics

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