Abstract 16529: Molecular and Functional Characterization of an Ultra Rare Frame-shift Mutation in CALR-encoded Calreticulin as a Probable Long QT Syndrome-susceptibility Variant
Introduction: Long QT syndrome (LQTS) is the most common, autosomal dominant, sudden death predisposing cardiac channelopathy. Although 17 LQTS genes have been discovered, 20% of LQTS remains genetically elusive. Whole exome sequencing (WES) followed by a strategic, knowledge-based variant filtration approach may elucidate novel LQTS-susceptibility genes.
Methods: A LQTS family with multiple sudden deaths was referred for genetic evaluation. The index case was a 21-year-old male who died suddenly but had a pre-mortem ECG with marked QT prolongation. The decedent’s mother also showed QT prolongation. Only paraffin embedded tissue (PET) was available from the decedent, so the mother’s DNA was analyzed by WES. Following WES, variants were filtered using Ingenuity Variant Analysis (IVA) software. Only non-synonymous variants with a quality score >20, read-depth >10, and absent in ExAC were considered. Further filtration was performed using IVA’s biological context pathway analysis set to capture genes most likely related to LQTS. Electrophysiological studies were performed on the variant with highest probability of pathogenicity.
Results: Following WES and variant filtration, only a CALR frame-shift variant (R376fs/10) remained as a probable LQTS mutation. No radical CALR variants reside in ExAC’s 60,000+ exomes. The mutation was confirmed in the decedent’s PET-derived DNA. CALR-encoded calreticulin (CRT) is a Ca2+ binding chaperone of the endoplasmic reticulum. Both knockout and over-expression of CRT exert extreme effects on the murine cardiac system, including sudden death. Recently, CRT has been linked with altered L-type calcium (LTCC) ion channel activity. Wild-type (WT)-CALR reduced Cav1.2 peak current density by 43.1%. In contrast, CALR-R376fs/10 mutation reversed this Cav1.2 inhibition and caused a net gain-of-function of Cav1.2 channel current compared with CALR-WT co-expression (64.2% increase). No pathogenic variants in CALR were identified in 25 additional, unrelated, genetically elusive LQTS cases.
Conclusion: Mutations in CALR-encoded calreticulin may be a rare cause of autosomal dominant LQTS precipitated in part by an accentuation of the LTCC, thereby potentially mimicking CACNA1C-mediated LQTS.
Author Disclosures: C.M. Gibbs: Consultant/Advisory Board; Modest; Boston Scientific, Gilead Sciences, Medtronic, St. Jude. Other; Significant; Transgenomic.
- © 2015 by American Heart Association, Inc.