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... 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. Show less
