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12-lead ECG recorded at admission. Sinus rhythm 58 bpm. PR: 140 ms. QRS: 80 ms, normal axis. Prolongation of QT interval with an obvious bifid T wave in precordial lead V2-V3, and a subtle bifid T wave in V4-V6. QTc: 560 ms.
Source publication
We report the case of a woman with syncope and persistently prolonged QTc interval. Screening of congenital long QT syndrome (LQTS) genes revealed that she was a heterozygous carrier of a novel KCNH2 mutation, c.G238C. Electrophysiological and biochemical characterizations unveiled the pathogenicity of this new mutation, displaying a 2-fold reducti...
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Context 1
... adrenergic stimulation. Outpatient cardiac evaluation showed a prolonged QT interval, QTc values of 536 ms to 575 ms, and variations in T wave morphology. Echocardiography revealed very mild mitral valve regurgitation with no evidence of valvular prolapse. Cardiac assessment upon admission to our hospital confirmed the prolonged QT interval (Fig. 1, QT = 560 ms) and showed bifid T waves in precordial leads. During exercise testing no further QT prolongation was measured ( Fig. 2), suggesting a limited risk during exercise activities in accordance with the clinical history of the patient. Because patient's ECG recorded at admission was consistent with congenital LQTS, and more ...
Context 2
... adrenergic stimulation. Outpatient cardiac evaluation showed a prolonged QT interval, QTc values of 536 ms to 575 ms, and variations in T wave morphology. Echocardiography revealed very mild mitral valve regurgitation with no evidence of valvular prolapse. Cardiac assessment upon admission to our hospital confirmed the prolonged QT interval (Fig. 1, QT = 560 ms) and showed bifid T waves in precordial leads. During exercise testing no further QT prolongation was measured ( Fig. 2), suggesting a limited risk during exercise activities in accordance with the clinical history of the patient. Because patient's ECG recorded at admission was consistent with congenital LQTS, and more ...
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Citations
... [15][16][17] 178/211 (84%) KCNH2 variants associated with LQT2 whose cell surface abundance has been assayed have defective trafficking to the cell surface ( Figure 1C). [18][19][20][21][22][23][24][25][26][27][28] . CC-BY-NC-ND 4.0 International license author/funder. ...
Background: KCHN2 encodes the KV11.1 potassium channel responsible for IKr, a major repolarization current during the cardiomyocyte action potential. Variants in KCNH2 that decrease IKr can cause Type 2 Long QT syndrome, usually due to mistrafficking to the cell surface. Accurately discriminating between variants with normal and abnormal trafficking would help clinicians identify and treat individuals at risk of a major cardiac event. The volume of reported non-synonymous KCNH2 variants preclude the use of conventional electrophysiologic methods for functional study.
Objective: To report a high-throughput, multiplexed screening method for KCNH2 genetic variants capable of measuring the cell surface abundance of hundreds of missense variants in KCNH2.
Methods: We develop a method to quantitate KCNH2 variant trafficking on a pilot region of 11 residues in the S5 helix, and generate trafficking scores for 220/231 missense variants in this region.
Results: For 5/5 variants, high-throughput trafficking scores validated when tested in single variant flow cytometry and confocal microscopy experiments. We additionally compare our results with planar patch electrophysiology and find that loss-of-trafficking variants do not produce IKr, but that some variants which traffic normally may still be functionally compromised.
Conclusions: Here, we describe a new method for detecting trafficking-deficient variants in KCNH2 in a multiplexed assay. This new method accurately generates trafficking data for variants in KCNH2 and can be readily extended to all residues in Kv11.1 and to other cell surface proteins.
