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

Copier, Jaël S and Bootsma, Marianne and Ng, Chai A and Wilde, Arthur A M and Bertels, Robin A and Bikker, Hennie and Christiaans, Imke and van der Crabben, Saskia N and Hol, Janna A and Koopmann, Tamara T and Knijnenburg, Jeroen and Lommerse, Aafke A J and van der Smagt, Jasper J and Bezzina, Connie R and Vandenberg, Jamie I and Verkerk, Arie O and Barge-Schaapveld, Daniela Q C M and Lodder, Elisabeth M (2022) Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance. Human Molecular Genetics, 32 (7). pp.1072-1082. ISSN 0964-6906

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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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 27 Apr 2023 04:22
Last Modified: 27 Apr 2023 04:22

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