Dan Hu1, Yang Li2, Jiancheng Zhang3, Ryan Pfeiffer4, Michael H Gollob5, Jeff Healey6, Daniel Toshio Harrell7, Naomasa Makita7, Haruhiko Abe8, Yaxun Sun9, Jihong Guo10, Li Zhang11, Ganxin Yan11, Douglas Mah12, Edward P Walsh12, Harris B Leopold13, Carla Giustetto14, Fiorenzo Gaita14, Agnieszka Zienciuk-Krajka15, Andrea Mazzanti16, Silvia G Priori17, Charles Antzelevitch11, Hector Barajas-Martinez18. 1. Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China; Molecular Genetics Department, Masonic Medical Research Laboratory, Utica, New York. Electronic address: dianah@mmrl.edu. 2. Institute of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China. 3. Department of Cardiology, Provincial Clinical Medicine College of Fujian Medical University, Fujian, China. 4. Molecular Genetics Department, Masonic Medical Research Laboratory, Utica, New York. 5. Department of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada. 6. Population Health Research Institute, McMaster University, Hamilton, ON, Canada. 7. Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 8. Department of Heart Rhythm Management, University of Occupational and Environmental Health, Fukuoka, Japan. 9. Sir Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China. 10. Department of Cardiac Electrophysiology, Division of Cardiology, People's Hospital, Peking University, Beijing, China. 11. Lankenau Institute for Medical Research and Jefferson Medical College, Philadelphia, Pennsylvania. 12. Cardiac Electrophysiology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 13. Connecticut Children's Medical Center, University of Connecticut School of Medicine, Hartford, Connecticut. 14. Division of Cardiology, University of Torino, Department of Medical Sciences, "Città della Salute e della Scienza" Hospital, Torino, Italy. 15. Department of Cardiology and Electrotherapy, Medical University of Gdansk, Gdansk, Poland. 16. Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy. 17. Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy. 18. Molecular Genetics Department, Masonic Medical Research Laboratory, Utica, New York. Electronic address: barajash@mmrl.edu.
Abstract
OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques. RESULTS: KCNH2-T618I was identified in 18 members of 7 unrelated families (10 men; median age: 24.0 years). All carriers showed 100% penetrance with variable expressivity. Eighteen members in 7 families had SCD. The average QTc intervals of probands and all carriers was 294.1 ± 23.8 ms and 313.2 ± 23.8 ms, respectively. Seven carriers received an implantable cardioverter-defibrillator. Quinidine with adequate plasma levels was effective in prolonging QTc intervals among 5 cases, but 3 cases still had premature ventricular contraction or nonsustained ventricular tachycardia. Bepridil successfully prevented drug-refractory ventricular fibrillation in 1 case with 19-ms prolongation of the QTc interval. Functional studies with KCNE2 revealed a significant increase of IKr (rapidly activating delayed rectifier potassium channel) tail-current density in homozygous (119.0%) and heterozygous (74.6%) expression compared with WT. AP clamp recordings showed IKr was larger, and peak repolarizing current occurred earlier in mutant versus WT channels. CONCLUSIONS: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.
OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques. RESULTS:KCNH2-T618I was identified in 18 members of 7 unrelated families (10 men; median age: 24.0 years). All carriers showed 100% penetrance with variable expressivity. Eighteen members in 7 families had SCD. The average QTc intervals of probands and all carriers was 294.1 ± 23.8 ms and 313.2 ± 23.8 ms, respectively. Seven carriers received an implantable cardioverter-defibrillator. Quinidine with adequate plasma levels was effective in prolonging QTc intervals among 5 cases, but 3 cases still had premature ventricular contraction or nonsustained ventricular tachycardia. Bepridil successfully prevented drug-refractory ventricular fibrillation in 1 case with 19-ms prolongation of the QTc interval. Functional studies with KCNE2 revealed a significant increase of IKr (rapidly activating delayed rectifier potassium channel) tail-current density in homozygous (119.0%) and heterozygous (74.6%) expression compared with WT. AP clamp recordings showed IKr was larger, and peak repolarizing current occurred earlier in mutant versus WT channels. CONCLUSIONS: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Eduardo Back Sternick; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti MacIntyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Juan Pablo Ochoa; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: Europace Date: 2022-09-01 Impact factor: 5.486
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Authors: Laura S Raschwitz; Ibrahim El-Battrawy; Kim Schlentrich; Johanna Besler; Michael Veith; Gretje Roterberg; Volker Liebe; Rainer Schimpf; Siegfried Lang; Christian Wolpert; Xiaobo Zhou; Ibrahim Akin; Martin Borggrefe Journal: Front Genet Date: 2020-01-17 Impact factor: 4.599
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