The variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to β-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under β-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under β-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to β-blocker therapy.

Department of Biomedical Engineering Faculty of Electrical Engineering and Communication Brno University of Technology Technická 10 616 00 Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Kotlářská 267 2 611 37 Brno Czech Republic

Department of Internal Medicine and Cardiology University Hospital Brno and Faculty of Medicine Masaryk University Jihlavská 20 625 00 Brno Czech Republic

Department of Medical Genetics University Hospital Brno and Faculty of Medicine Masaryk University Jihlavská 20 625 00 Brno Czech Republic

Department of Paediatrics University Hospital Brno and Faculty of Medicine Masaryk University Černopolní 9 613 00 Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

Division of Biologically Active Complexes and Molecular Magnets Regional Centre of Advanced Technologies and Materials Faculty of Science Palacký University in Olomouc Šlechtitelů 27 783 71 Olomouc Czech Republic

Institute of Thermomechanics Czech Academy of Sciences Dolejškova 5 182 00 Prague Czech Republic

Repromeda Clinic for Reproductive Medicine and Preimplantation Genetic Diagnosis Biology Park Studentská 812 6 625 00 Brno Czech Republic

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Sci Rep. 2021 Apr 29;11(1):9597. doi: 10.1038/s41598-021-89234-z. PubMed

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