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Multiple arrhythmic syndromes in a newborn, owing to a novel mutation in SCN5A

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Background. Mutations in the SCN5A gene have been linked to Brugada syndrome (BrS), conduction disease, Long QT syndrome (LQT3), atrial fibrillation (AF), and to pre- and neonatal ventricular arrhythmias. Objective. The objective of this study is to characterize a novel mutation in Nav1.5 found in a newborn with fetal chaotic atrial tachycardia, post-partum intraventricular conduction delay, and QT interval prolongation. Methods. Genomic DNA was isolated and all exons and intron borders of 15 ion-channel genes were sequenced, revealing a novel missense mutation (Q270K) in SCN5A. Nav1.5 wild type (WT) and Q270K were expressed in CHO-K1 with and without the Navβ1 subunit. Results. Patch-clamp analysis showed ∼40% reduction in peak sodium channel current (I Na) density for Q270K compared with WT. Fast and slow decay of I Na were significantly slower in Q270K. Steady-state activation and inactivation of Q270K channels were shifted to positive potentials, and window current was increased. The tetrodotoxin-sensitive late I Na was increased almost 3-fold compared with WT channels. Ranolazine reduced late I Na in WT and Q270K channels, while exerting minimal effects on peak I Na. Conclusion. The Q270K mutation in SCN5A reduces peak I Na while augmenting late I Na, and may thus underlie the development of atrial tachycardia, intraventricular conduction delay, and QT interval prolongation in an infant.

Keywords: Brugada syndrome; LQT syndrome; Nav1.5; arrhythmia; arythmie; atrial fibrillation; electrophysiology; fibrillation auriculaire; genetics; génétique; neonate; nouveau-né; syndrome LQT; syndrome de Brugada; électrophysiologie

Document Type: Research Article


Affiliations: 1: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. 2: Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA. 3: Duke University Medical Center, Durham, NC 27710, USA.

Publication date: October 9, 2011

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