2017 Cardiovascular Research Day Abstract Book

35
Identification of Candidate Long QT Syndrome Type 2 Patients Starting from Exome
Sequences Identified in a Biobank Cohort
Allison Hall, MS 1 • Don Burgess, PhD 2 • Pierre Fwelo 1 • Jennifer Smith 3 • Corey Anderson, PhD 4 •
Craig T. January, MD, PhD 4 • Ann Stepanchick, PhD 4 • Uyenlinh Mirshah, PhD 4 • Jonathan Luo, PhD 4
• Dustin Hartzel, PhD 4 • Michael Murray, MD 5 • Tooraj Mirshahi, PhD 5 • Brian Delisle, PhD 1
1Physiology, University of Kentucky • 2 Physics, Asbury • 3 University of Kentucky • 4 University of
Wisconsin • 5 Geisinger Health System
Staff
Introduction: Every year congenital long QT syndrome (LQTS) is thought to cause sudden cardiac
death in hundreds of individuals in the US. Genetic screening potentially could identify LQTS
patients before it strikes. However, genetic analyses often find novel rare sequence variants of
uncertain physiological significance, and little is known about genetic screening in unaffected
populations.
Hypothesis: LQTS type 2 (LQT2) is caused by loss-of-function mutations in the rapidly activating
delayed rectifier K+ channel gene KCNH2 (Kv11.1). Screening for KCNH2 variants using an
approach similar to the Comprehensive In Vitro Proarrhythmia Assay for drug testing will allow the
identification of candidate LQT2 patients starting from exome sequences.
Methods: Ten KCNH2 mutations from the NCBI ClinVar database listed as “pathogenic”, “suspectedpathogenic”,
or “conflicting interpretations” were identified in 10,000 Whole Exome Sequences
(WES) from the Geisinger MyCode® cohort. The KCNH2 mutations were screened using Western
blot to quantify terminally glycosylated mature Kv11.1 protein (a proxy for Kv11.1 channel
trafficking); patch-clamp to measure Kv11.1 channel current (IKv11.1); and computational
simulations with a human ventricular action potential (AP) model to predict AP duration (a
correlate for the QT interval).
Results: Two of the KCNH2 mutations were trafficking-deficient to decrease mature Kv11.1 protein
and peak IKv11.1, and five mutations altered normal Kv11.1 channel activation or deactivation.
Simulating the decrease in IKv11.1 caused by the trafficking-deficient KCNH2 mutations increased
AP duration by >30%, whereas the mutations that disrupted Kv11.1 channel gating did not predict
significant changes in AP duration. De-identified Electronic Health Records (EHR) from the
Geisinger MyCode® subjects showed that the corrected QT interval (QTc Bazette) for the patients
that harbored the trafficking-deficient KCNH2 mutations was ≥480 ms, whereas the average QTc
for all EHR database subjects was