Novel Calmodulin Mutations Cause Congenital Long QT Syndrome and Affect Calcium Current in Human Cardiomyocytes

Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the congenital long QT syndrome (LQTS). We identified two novel CaM mutations in children with LQTS associated with cardiac arrest, and performed studies to elucidate the functional consequences of each molecular defect. The first mutation was discovered in a male infant with a ventricular septal defect and fetal bradycardia born to healthy parents. His ECG on postnatal day 1 revealed bradycardia and very prolonged QTc (651 msec). At age 2-days, he developed 2:1 AV block, profound bradycardia (50 bpm) and cardiogenic shock. He was resuscitated and received a pacemaker. Targeted DNA sequencing revealed a de novo mutation in CALM2 (D132H). A second novel mutation was discovered in a three year-old boy who suffered witnessed cardiac arrest. His initial rhythm was ventricular fibrillation, and after successful defibrillation an ECG recording revealed a QTc of 574 msec. The parents were healthy with normal QTc intervals....