Abstract 13371: CALM2 Mutations Associated With Atypical Juvenile Long QT Syndrome
Background: Congenital long QT syndrome (LQTS) is a monogenic predisposition to lethal cardiac arrhythmias.Despite decades of investigation and discovery of multiple responsible genes, a molecular etiology remains unknown in many LQTS cases.
Methods: We employed next-generation sequencing approaches (targeted exon capture, exome sequencing) along with conventional targeted mutation screening in three cohorts of LQTS probands without identified genetic causes.
Results: We identified three novel de novo missense mutations in CALM2, one of three human genes encoding identical calmodulin polypeptides.One mutation (p.D134H) was identified by targeted exon sequencing of 12 Japanese LQTS probands. This mutation was found in a girl who presented at age 19 months with syncope and a long QTc (579 ms) followed by several pisodes of cardiac arrest. ECG features and treatment responses were consistent with LQT3 but no SCN5A mutations were identified. Another CALM2 mutation (p.N98S) was discovered by analyzing exomes of 190 genotype-negative Japanese LQTS probands. This mutation was present in a 5 year-old boy with multiple episodes of exercise-induced syncope and dizziness along with a QTc of 520 ms consistent with LQT1. Interestingly, p.N98S mutation in a different calmodulin gene (CALM1) was previously associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in an Iraqi child. Finally, mutation CALM2-p.D132E was discovered by targeted screening of CALM1-3 in an adult female of European ancestry with a history of perinatal bradycardia and a diagnosis of neonatal LQTS who later exhibited clinical features consistent with CPVT at age 9 years. All mutations affect highly conserved residues located within the third (p.N98S) or forth (p.D132E, p.D134H) calcium binding loops, and recombinant mutant calmodulins exhibited reduced calcium binding affinity (p.N98S, 3.3-fold; p.D134H, 9.7-fold; p.D132E,18.5-fold).
Conclusions: CALM2 mutations are associated with early onset LQTS having overlapping clinical features of LQT1, LQT3 and CPVT suggesting the possibility of multiple ion channel targets of dysfunctional calmodulins.
- © 2013 by American Heart Association, Inc.