Abstract 14699: Spectrum and Prevalence of CALM1, CALM2, and CALM3 Mutations in Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Idiopathic Ventricular Fibrillation, and Sudden Unexplained Death in the Young
Introduction: Cardiac channelopathies such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) may lead to potentially lethal ventricular fibrillation and sudden unexplained death in the young (SUDY, 1-35 years of age). Two of the three genes (CALM1 and CALM2) that encode for calmodulin have been implicated recently in LQTS and CPVT and associate with a very malignant phenotype with early onset typically within the first decade of life. Therefore, given its apparent early and malignant expressivity, we set out to determine the spectrum and prevalence of CALM1, CALM2, and CALM3 mutations in LQTS, CPVT, idiopathic ventricular fibrillation (IVF), and SUDY.
Methods: Using PCR, DHPLC, and direct DNA sequencing, a comprehensive coding region mutational analysis of CALM1, CALM2 and CALM3 was performed on genomic DNA isolated from 39 unrelated LQTS, 13 CPVT, 16 IVF, and 107 SUDY cases that remained genotype-negative following KCNQ1, KCNH2, SCN5A, and RYR2 analysis. To be considered a potential pathogenic mutation, identified variants had to be non-synonymous and absent among three publicly available exome databases (1000 Genomes Project, NHLBI Exome Sequencing Project, and 12000 Exome Chip).
Results: Six missense CALM1 or CALM2 mutations were found in 6 cases (LQTS, 3/39 [7.7%], 1 male; SUDY, 3/107 [2.8%], 2 males). Two of the mutations (N54I-CALM1 and D96V-CALM2) were reported in the original discoveries and have been functionally characterized as abnormal. All 3 LQTS patients manifested a severe phenotype (QTc > 550 ms, 2 with cardiac arrest). The yield of CALM1/CALM2 mutations was significantly higher among cases ≤ 10 years of age compared to those case > 10 years (LQTS, 3/12 [25%] vs. 0/27 [0%], p = 0.04; SUDY, 3/29 [10%] vs. 0/78 [0%], p = 0.02). A novel CALM3 mutation (A103V) was identified in a 12-year-old female with CPVT.
Conclusion: Calmodulin-mediated channelopathies potentially account for up to 25% of otherwise genetically elusive and severe LQTS and 10% of genotype-negative SUDY cases under the age of 10 years. Here in, we also report for the first time a CALM3 mutation identified in a single case of CPVT. The pedigree expansion and functional characterization of the novel calmodulin mutations are currently underway.
- © 2013 by American Heart Association, Inc.