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Clinical and functional characterisation of a recurrent KCNQ1 variant in the Belgian population.
Sieliwonczyk, Ewa; Alaerts, Maaike; Simons, Eline; Snyders, Dirk; Nijak, Aleksandra; Vandendriessche, Bert; Schepers, Dorien; Akdeniz, Dogan; Van Craenenbroeck, Emeline; Knaepen, Katleen; Rabaut, Laura; Heidbuchel, Hein; Van Laer, Lut; Saenen, Johan; Labro, Alain J; Loeys, Bart.
Afiliação
  • Sieliwonczyk E; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium. ewa.sieliwonczyk@uantwerpen.be.
  • Alaerts M; Medical Genetics (MEDGEN), GENCOR, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. ewa.sieliwonczyk@uantwerpen.be.
  • Simons E; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Snyders D; Medical Genetics (MEDGEN), GENCOR, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • Nijak A; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Vandendriessche B; Experimental Neurobiology Unit, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • Schepers D; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Akdeniz D; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Van Craenenbroeck E; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Knaepen K; Medical Genetics (MEDGEN), GENCOR, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • Rabaut L; Experimental Neurobiology Unit, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • Heidbuchel H; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Van Laer L; Department of Cardiology, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Saenen J; Cardiovascular Research, GENCOR, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • Labro AJ; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • Loeys B; Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Orphanet J Rare Dis ; 18(1): 23, 2023 01 31.
Article em En | MEDLINE | ID: mdl-36721196
ABSTRACT

BACKGROUND:

The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on the molecular, clinical and functional characterization of the KCNQ1 c.1124_1127delTTCA variant.

RESULTS:

Forty-one heterozygous variant harboring individuals demonstrated a predominantly mild clinical and electrophysiological phenotype, compared to individuals harboring other KCNQ1 pathogenic variants (5% symptomatic before 40 years of age, compared to 24% and 29% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers, respectively, 33% with QTc ≤ 440 ms compared to 10% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers). The LQTS phenotype was most comparable to that observed for the Swedish p.(Arg518*) founder mutation (7% symptomatic at any age, compared to 17% in p.(Arg518*) variant carriers, 33% with QTc ≤ 440 ms compared to 16% in p.(Arg518*) variant carriers). Surprisingly, short tandem repeat analysis did not reveal a common haplotype for all families. One KCNQ1 c.1124_1127delTTCA harboring patient was diagnosed with Brugada syndrome (BrS). The hypothesis of a LQTS/BrS overlap syndrome was supported by electrophysiological evidence for both loss-of-function and gain-of-function (acceleration of channel kinetics) in a heterologous expression system. However, BrS phenotypes were not identified in other affected individuals and allelic KCNQ1 expression testing in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed nonsense mediated decay of the c.1124_1127delTTCA allele.

CONCLUSIONS:

The c.1124_1127delTTCA frameshift variant shows a high prevalence in our region, despite not being confirmed as a founder mutation. This variant leads to a mild LQTS phenotype in the heterozygous state. Despite initial evidence for a gain-of-function effect based on in vitro electrophysiological assessment in CHO cells and expression of the KCNQ1 c.1124_1127delTTCA allele in patient blood cells, additional testing in iPSC-CMs showed lack of expression of the mutant allele. This suggests haploinsufficiency as the pathogenic mechanism. Nonetheless, as inter-individual differences in allele expression in (iPSC-) cardiomyocytes have not been assessed, a modifying effect on the BrS phenotype through potassium current modulation cannot be excluded.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome do QT Longo / Canal de Potássio KCNQ1 Tipo de estudo: Risk_factors_studies Limite: Animals / Humans País como assunto: Europa Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome do QT Longo / Canal de Potássio KCNQ1 Tipo de estudo: Risk_factors_studies Limite: Animals / Humans País como assunto: Europa Idioma: En Ano de publicação: 2023 Tipo de documento: Article