Leiden University Scholarly Publications

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Brink, A.H. van den (2022)

Using human pluripotent stem cell-derived cardiomyocytes to understand genetic variant pathogenicity in the ion channelopathy LQT2

Doctoral Thesis
One of the main challenges in the clinical management of patients with monogenic cardiac disease patients is the clinical heterogeneity in disease severity. Clinical manifestation of congenital long QT syndrome type 2 (LQT2) can range from the absence of symptoms to life-threatening arrhythmia episodes. Insight into the genetic etiology could advance clinical-decision making and guide the development of tailored medicine strategies. The focus of this thesis was twofold, 1) to validate technical procedures to store hiPSC-CMs and 2) to investigate genetic variant pathogenicity and unravel variable disease expressivity in genetically-matched hiPSC-CM models with LQT2-associated variants. First we established cryopreservation as an opportune method to store hiPSC-CMs with molecular and functional characteristics being retained after thaw and recovery. Second, we demonstrate the potential of hiPSC-CMs to reveal the inherent severity of KCNH2 mutations when using genetically-matched...Show moreOne of the main challenges in the clinical management of patients with monogenic cardiac disease patients is the clinical heterogeneity in disease severity. Clinical manifestation of congenital long QT syndrome type 2 (LQT2) can range from the absence of symptoms to life-threatening arrhythmia episodes. Insight into the genetic etiology could advance clinical-decision making and guide the development of tailored medicine strategies. The focus of this thesis was twofold, 1) to validate technical procedures to store hiPSC-CMs and 2) to investigate genetic variant pathogenicity and unravel variable disease expressivity in genetically-matched hiPSC-CM models with LQT2-associated variants. First we established cryopreservation as an opportune method to store hiPSC-CMs with molecular and functional characteristics being retained after thaw and recovery. Second, we demonstrate the potential of hiPSC-CMs to reveal the inherent severity of KCNH2 mutations when using genetically-matched lines with KCNH2 mutations either located in different regions of the affected cardiac ion channel, in conjunction with a common single nucleotide, or a compound heterozygous mutation.
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Cardiac arrhythmia
Long QT syndrome
Disease modeling
Cardiac electrophysiology
Human induced pluripotent stem cell-derived cardiomyocytes
Genetic pathogenicity
Isogenic
All authors
Brink, A.H. van den
Supervisor
Mummery, C.L.
Co-supervisor
Davis, R.P.
Committee
Goumans, M.J.T.H.; Geijsen, N.; Passier, P.C.J.J.; Remme, C.A.
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2022-09-01
ISBN (print)
9789464195132

Funding

Sponsorship
The research described in the thesis was supported by a Starting Grant (STEMCARDIORISK) from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation programme, a VIDI fellowship from The Netherlands Organisation for Scientific Research [Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)], and The Netherlands Organ-on-Chip Initiative, an NWO Gravitation project funded by the Ministry of Education, Culture and Science of the government of The Netherlands.