The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome
Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved..
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.
| Errataetall: |
CommentIn: JACC Clin Electrophysiol. 2017 Jul;3(7):744-746. - PMID 28966985 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
JACC. Clinical electrophysiology - 3(2017), 7 vom: 19. Juli, Seite 727-743 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hu, Dan [VerfasserIn] |
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| Links: |
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| Themen: |
Channelopathy |
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| Anmerkungen: |
Date Completed 09.07.2019 Date Revised 09.07.2019 published: Print-Electronic CommentIn: JACC Clin Electrophysiol. 2017 Jul;3(7):744-746. - PMID 28966985 Citation Status MEDLINE |
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| doi: |
10.1016/j.jacep.2016.11.013 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM284061816 |
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| 100 | 1 | |a Hu, Dan |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome |
| 264 | 1 | |c 2017 | |
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| 500 | |a Date Completed 09.07.2019 | ||
| 500 | |a Date Revised 09.07.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: JACC Clin Electrophysiol. 2017 Jul;3(7):744-746. - PMID 28966985 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS) | ||
| 520 | |a BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a channelopathy | |
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| 650 | 4 | |a short QT syndrome | |
| 650 | 4 | |a sudden cardiac death | |
| 650 | 4 | |a therapy | |
| 650 | 7 | |a ERG1 Potassium Channel |2 NLM | |
| 650 | 7 | |a KCNH2 protein, human |2 NLM | |
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