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

Autor:	Copier JS; Experimental Cardiology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam, The Netherlands.; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart'., Bootsma M; Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 Leiden, The Netherlands., Ng CA; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia., Wilde AAM; Experimental Cardiology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam, The Netherlands.; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart'., Bertels RA; Department of Paediatric Cardiology, Leiden University Medical Center, Willem-Alexander Children's Hospital, Albinusdreef 2, 2333 Leiden, Netherlands., Bikker H; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart'.; Human Genetics, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands., Christiaans I; Department of Clinical Genetics, University Medical Centre Groningen, 9713GZ Groningen, The Netherlands., van der Crabben SN; Human Genetics, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands., Hol JA; Erasmus MC, Clinical Genetics, Doctor Molewaterplein 40, 3015 Rotterdam, The Netherlands., Koopmann TT; Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 Leiden, The Netherlands., Knijnenburg J; Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 Leiden, The Netherlands., Lommerse AAJ; Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 Leiden, The Netherlands., van der Smagt JJ; Clinical Genetics, University Medical Center Utrecht, Lundlaan 6, Utrecht, The Netherlands., Bezzina CR; Experimental Cardiology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam, The Netherlands.; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart'., Vandenberg JI; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia., Verkerk AO; Experimental Cardiology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam, The Netherlands.; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart'.; Medical Biology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands., Barge-Schaapveld DQCM; Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 Leiden, The Netherlands., Lodder EM; Experimental Cardiology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam, The Netherlands.; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart'.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2023 Mar 20; Vol. 32 (7), pp. 1072-1082.
DOI:	10.1093/hmg/ddac261
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press.)
Databáze:	MEDLINE
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