Reclassification of a likely pathogenic Dutch founder variant in KCNH2: implications of reduced penetrance

Jaël S. Copier*, Marianne Bootsma, Chai A. Ng, Arthur A.M. Wilde, Robin A. Bertels, Hennie Bikker, Imke Christiaans, Saskia N. van der Crabben, Janna A. Hol, Tamara T. Koopmann, Jeroen Knijnenburg, Aafke A.J. Lommerse, Jasper J. van der Smagt, Connie R. Bezzina, Jamie I. Vandenberg, Arie O. Verkerk, Daniela Q.C.M. Barge-Schaapveld, Elisabeth M. Lodder*

*Corresponding author for this work

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BACKGROUND: Variants in KCNH2, encoding the human ether a-go-go (hERG) channel that 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 independently by manual-, and automated calibrated patch clamp. 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) were used for manual patching. Automated patch clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. 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 with KCNH2-WT. Assessment of KCNH2-p.S906L-Hz by calibrated automatic patch clamp assay 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.

Original languageEnglish
Pages (from-to)1072-1082
Number of pages11
JournalHuman Molecular Genetics
Issue number7
Publication statusPublished - 1 Apr 2023

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