Senior Researcher, Geisinger Clinic
1 active project
Scientific Questions Being Studied
Life threatening cardiac arrhythmias can arise from genetic variants in ion channels. Long QT syndrome (LQTS) is an arrhythmia that is due to elongation of the ventricular action potential and can be caused by alterations in several genes, mainly channels, including several potassium channels and sodium channels as well as auxiliary subunits. In our research we have found that while missense variants in many of these channels maybe causal for LQTS, loss of function is not always associated or linked to a disease phenotype. The goal of this project is to assess the data set in all of us and explore the presence of loss of function mutations as well as missense mutations that we have found in other cohorts. We will explore whether these variants are linked to phenotypes consistent with LQTS.
- Disease Focused Research (Cardiac Arrhythmia )
We will use whole genome, exome and array data from All of Us to find previously identified misssense variants in several channel genes including: KCNJ2, KCNJ3, KCNH2, and KCNQ1.
We have found that several missions variants in these genes are most likely causal for LQTS, while loss of function variants such as early termination and frameshifts do not seem to contribute to the disease phenotype. We will annotate variants in these channel genes and use VEP and LOFTEE to determine their loss of function and in silico pathogenicity status. We will then examine existing data including diagnosis codes and electrocardiogram measures available for these patients to determine if they have LQTS.
We anticipate to determine whether simple loss of function in several ion channels contributes to LQTS. The All of Us data will be used to corroborate data that we have from other populations where we suspect a complex relationship between loss of function and missense variant and LQTS. Our findings will shed light on best practices to identify truly pathogenic genetic variants in these ion channels that can lead to arrhythmias. Proper utility of this approach will help identify patients who are truly at risk of developing potentially life-threatening arrhythmias and providing them with options to mitigate risk of future episodes
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set UsedControlled Tier
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