TY - JOUR T1 - Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance JF - bioRxiv DO - 10.1101/2022.08.05.502917 SP - 2022.08.05.502917 AU - J.S. Copier AU - M. Bootsma AU - C. Ng AU - A.A.M. Wilde AU - R.A. Bertels AU - H. Bikker AU - I. Christiaans AU - S.N. van der Crabben AU - J.A. Hol AU - T.T. Koopmann AU - J. Knijnenburg AU - A.A.J. Lommerse AU - J.J. van der Smagt AU - C.R. Bezzina AU - J.I. Vandenberg AU - A.O. Verkerk AU - D.Q.C.M. Barge-Schaapveld AU - E.M. Lodder Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/08/05/2022.08.05.502917.abstract N2 - Background Variants in KCNH2, encoding the hERG channel which is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to Long QT Syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C>T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making.Methods A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed by manual whole-cell patch-clamp using HEK293a cells expressing: (I) wild type (WT) KCNH2, (II) KCNH2-p.S906L alone (homozygous, Hm) or (III) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz). A calibrated automated patch-clamp assay using Flp-In HEK293 was used to follow up on the functional data.Results Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2, or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch-clamp showed a reduced current density by 69.8%, and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared to KCNH2-WT. Assessment of KCNH2-p.S906L-Hz, by calibrated automatic patch-clamp showed a reduction in current density by 35.6%.Conclusion The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss of function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.Competing Interest StatementA.A.M.W: consultant LQT therapeutics. ER -