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

Copier, J. S.; Bootsma, M.; Ng, C. A.; Wilde, A. A. M.; Bertels, R. A.; Bikker, H.; Christiaans, I.; van der Crabben, S. N.; Hol, J. A.; Koopmann, T. T.; Knijnenburg, J.; Lommerse, A. A. J.; van der Smagt, J. J.; Bezzina, C. R.; Vandenberg, J. I.; Verkerk, A. O.; Barge-Schaapveld, D. Q. C. M.; Lodder, E. M.

doi:10.1101/2022.08.05.502917

bioRxiv · 10.1101/2022.08.05.502917

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

Copier, J. S.·Bootsma, M.·Ng, C. A.·Wilde, A. A. M.·Bertels, R. A.·Bikker, H.·Christiaans, I.·van der Crabben, S. N.·Hol, J. A.·Koopmann, T. T.·Knijnenburg, J.·Lommerse, A. A. J.·van der Smagt, J. J.·Bezzina, C. R.·Vandenberg, J. I.·Verkerk, A. O.·Barge-Schaapveld, D. Q. C. M.·Lodder, E. M.

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Abstract

BackgroundVariants 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. MethodsA 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. ResultsIncomplete 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%. ConclusionThe 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.

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Copier, J. S., Bootsma, M., Ng, C. A., Wilde, A. A. M., Bertels, R. A., Bikker, H., Christiaans, I., van der Crabben, S. N., Hol, J. A., Koopmann, T. T., Knijnenburg, J., Lommerse, A. A. J., van der Smagt, J. J., Bezzina, C. R., Vandenberg, J. I., Verkerk, A. O., Barge-Schaapveld, D. Q. C. M., Lodder, E. M.. 2022-08-05. Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance. https://doi.org/10.1101/2022.08.05.502917

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