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http://purl.uniprot.org/citations/36269083http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/36269083http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.org/dc/terms/identifier"doi:10.1093/hmg/ddac261"xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"van der Smagt J.J."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Vandenberg J.I."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Koopmann T.T."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Bezzina C.R."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Christiaans I."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Bikker H."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Lodder E.M."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Barge-Schaapveld D.Q.C.M."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Knijnenburg J."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Wilde A.A.M."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"van der Crabben S.N."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Verkerk A.O."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Ng C.A."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Bootsma M."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Copier J.S."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Hol J.A."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Bertels R.A."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/author"Lommerse A.A.J."xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/date"2023"xsd:gYear
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/name"Hum Mol Genet"xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/pages"1072-1082"xsd:string
http://purl.uniprot.org/citations/36269083http://purl.uniprot.org/core/title"Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance."xsd:string
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