Sadrieh, ArashDomanski, LukePitt-Francis, JoeMann, Stefan A.Hodkinson, Emily C.Ng, Chai AnnPerry, Matthew D.Taylor, JohnGavaghan, DavidSubbiah, Rajesh N.Vandenberg, Jamie I.Hill, Adam P2018-11-292018-11-292041-1723http://hdl.handle.net/1885/153533The heart rhythm disorder long QT syndrome (LQTS) can result in sudden death in the young or remain asymptomatic into adulthood. The features of the surface electrocardiogram (ECG), a measure of the electrical activity of the heart, can be equally variable in LQTS patients, posing well-described diagnostic dilemmas. Here we report a correlation between QT interval prolongation and T-wave notching in LQTS2 patients and use a novel computational framework to investigate how individual ionic currents, as well as cellular and tissue level factors, contribute to notched T waves. Furthermore, we show that variable expressivity of ECG features observed in LQTS2 patients can be explained by as little as 20% variation in the levels of ionic conductances that contribute to repolarization reserve. This has significant implications for interpretation of whole-genome sequencing data and underlies the importance of interpreting the entire molecular signature of disease in any given individualapplication/pdf201410.1038/ncomms60692018-11-29