Non-missense variants of KCNH2 show better outcomes in type 2 long QT syndrome

Abstract Aims More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients. Methods and results We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants—whether they cause HI or DN via altered functional domains—and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005). Conclusion Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2. Graphical Abstract Graphical Abstract AE, arrhythmia event; CI, confidence interval; CNBHD, cyclic nucleotide-binding homology domain; DN, dominant-negative; EAGD, ether-à-go-go domain; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; HR, hazard ratio; HI, haploinsufficiency; LOF, loss-of-function; LQT2, long QT syndrome type 2; mRNA, messenger RNA; NMD, nonsense mediated mRNA decay; PD, pore domain; pDN, predicted DN; pHI, predicted HI; PTC, premature termination codon; QTc, corrected QT interval; VSD, voltage sensor domain; WT, wild-type.