Briefly, paired-end libraries were prepared following the manufacturer's protocol (Illumina, San Diego, CA and Agilent, Santa Clara, CA) using the Bravo liquid handler from Agilent.
Whole Exome Sequencing (WES) with Targeted Calmodulin Gene AnalysisĪll 39 LQTS patients underwent WES and subsequent calmodulin (CaM) gene ( CALM1, CALM2, and CALM3) specific analysis. 7, 8, 10, 11 Here, we describe the spectrum, prevalence, and functional consequence of novel CaM variants identified within our cohort of 39 unrelated patients with genetically elusive LQTS. 9Īll of the identified LQTS-associated variants in CaM characterized to date have reduced affinity for Ca 2+ and attenuated Ca V1.2 inactivation through the loss of calcium dependent inactivation (CDI). 8 Finally, a variant was identified in CALM3-encoded CaM in a severe case of LQTS. Since then, additional CALM2 variants have also been identified in cases of LQTS and LQTS/CPVT overlap phenotypes. 7 Follow-up cohort analysis identified two additional LQTS patients with variants in CALM1. In 2013, whole exome sequencing (WES) was utilized on two parent-child trios of severe cases of LQTS presenting during infancy yielding de novovariants in CALM1 and CALM2. 7- 9 LQTS is a disorder of ventricular myocardial repolarization characterized by the prolongation of the heart-rate corrected QT interval (QTc) on a resting electrocardiogram (ECG), manifesting clinically as syncope, seizures, or sudden death in the setting of a structurally normal heart. Variants in all three of the calmodulin genes ( CALM1, CALM2, and CALM3) have been described recently in LQTS.
1- 3 Interestingly, there are three calmodulin genes, CALM1 (chr14q31), CALM2 (chr2p21), and CALM3 (chr19q13), 4 with unique nucleotide sequences that all encode for a completely identical 149 amino acid CaM protein, 5, 6 which are expressed differentially in the human heart. Calcium-induced activation of CaM regulates many calcium-dependent processes and modulates the function of cardiac ion channels including the long QT syndrome (LQTS)-associated CACNA1C-encoded Ca V1.2 calcium channel and SCN5A-encoded Na V1.5 sodium channel, as well as the catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RYR2-encoded ryanodine receptor. 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.Ĭalmodulin (CaM) is an essential Ca 2+ sensing, signal-transducing protein. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04% PConclusionsOverall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. 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 resultsThirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. All these interactions may play a role in disease pathogenesis. CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. These LQTS-causative variants reduce CaM affinity to Ca(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). BackgroundCalmodulin (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.
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