In:
Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 2 ( 2016-04), p. 136-146
Abstract:
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 (Ca V 1.2). CaM also modulates Na V 1.5 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 Ca V 1.2, mild accentuation in Na V 1.5 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.
Type of Medium:
Online Resource
ISSN:
1942-325X
,
1942-3268
DOI:
10.1161/CIRCGENETICS.115.001323
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2016
detail.hit.zdb_id:
2927603-2
detail.hit.zdb_id:
2457085-0
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