Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G
- Circ Cardiovasc Genet. 2016 Apr;9(2):136-146. doi: 10.1161/CIRCGENETICS.115.001323.
- 1. Department Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.
- 2. Department of Medicine, Vanderbilt University, Nashville, TN.
- 3. Departments of Biochemistry & Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN.
- 4. Mayo Medical School, Mayo Clinic, Rochester, MN.
- 5. Children's Hospital of Philadelphia, Philadelphia, PA.
- 6. Department of Pediatric Cardiology, Phoenix Children's Hospital, Phoenix, AZ.
- 7. Department of Pediatrics, Division of Pediatric Cardiology, University of Alabama at Birmingham, Birmingham, AL.
- 8. Division of Cardiology, Nicklaus Children's Hospital, Miami, FL.
- 9. Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
- 10. Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN.
- # Contributed equally.
Background: Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to CA(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants.
Methods and results: Thirty-eight genetically elusive LQTS cases underwent whole-exome Sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in CA(2+)-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release.
Conclusions: Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.