Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval.

Long QT syndrome (LQTS), an inherited cardiac arrhythmia syndrome with congenital and drug-induced presentations and known monogenic and polygenic contributions, represents a significant clinical challenge due to its complex genetic underpinning and propensity for fatal arrhythmias. In this study, we generated induced pluripotent stem cells (iPSCs) reprogrammed from peripheral blood mononuclear cells (PBMCs) of six patients with extreme polygenic scores for short and long corrected QT intervals. This patient-specific approach will enable us to better understand variable expressivity and penetrance of LQTS, using rigorously validated iPSC lines serve as a vital resource for elucidating the molecular mechanisms underlying LQTS.

An all-atom model of the human cardiac sodium channel in a lipid bilayer.

Voltage-gated sodium channels (Na) are complex macromolecular proteins that are responsible for the initial upstroke of an action potential in excitable cells. Appropriate function is necessary for many physiological processes such as heartbeat, voluntary muscle contraction, nerve conduction, and neurological function. Dysfunction can have life-threatening consequences.

Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance.

Multiplexed Assays of Variant Effect and Automated Patch-clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance.

Human disease-associated calmodulin mutations alter calcineurin function through multiple mechanisms.

Calmodulin (CaM) is a ubiquitous, calcium-sensing protein that regulates a multitude of processes throughout the body. In response to changes in [Ca], CaM modifies, activates, and deactivates enzymes and ion channels, as well as many other cellular processes. The importance of CaM is highlighted by the conservation of an identical amino acid sequence in all mammals.