| Title: |
Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance |
| Authors: |
Copier, JS; Bootsma, M; Ng, CA; Wilde, AAM; Bertels, RA; Bikker, H; Christiaans, I; van der Crabben, SN; Hol, JA; Koopmann, TT; Knijnenburg, J; Lommerse, AAJ; van der Smagt, JJ; Bezzina, CR; Vandenberg, JI; Verkerk, AO; Barge-Schaapveld, DQCM; Lodder, EM |
| Source: |
urn:ISSN:0964-6906 ; urn:ISSN:1460-2083 ; Human Molecular Genetics, 32, 7, 1072-1082 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2023 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
31 Biological Sciences; 3105 Genetics; Genetics; Pediatric Research Initiative; Heart Disease; Congenital Heart Disease; Rare Diseases; Cardiovascular; Humans; Long QT Syndrome; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Penetrance; Heart; ERG1 Potassium Channel; anzsrc-for: 31 Biological Sciences; anzsrc-for: 3105 Genetics; anzsrc-for: 06 Biological Sciences; anzsrc-for: 11 Medical and Health Sciences |
| Description: |
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 (I Kr ), 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_81656; https://doi.org/10.1093/hmg/ddac261 |
| DOI: |
10.1093/hmg/ddac261 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_81656; https://doi.org/10.1093/hmg/ddac261 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.DEDD6E7A |
| Database: |
BASE |