A mutation in CALM1 encoding calmodulin causes sudden cardiac death in childhood and adolescence

Abstract

Background: Although sudden cardiac death in childhood and adolescence is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Genetic testing therefore plays an important role in identifying individuals at risk. Methods and results: We characterized a Moroccan family presenting with a history of ventricular tachycardia and sudden death. Of seven siblings, two died suddenly at the ages of 9 and 10 years, and another two were resuscitated from out-of-hospital cardiac arrest (OHCA) at the ages of 10 and 16, respectively. ICDs were implanted in the latter two individuals; one of these individuals had recurrent self-limiting episodes of ventricular tachycardia and there were three ICD discharges for sustained episodes of VT/VF. Physical stress precipitated all the OHCA events. ECGs, exercise tests and 24-hour Holter monitoring did not reveal ectopic beats or arrhythmias but did show evidence of QTc interval prolongation at frequencies > 110 bpm (e.g. QTc = 501 ms at 143 bpm). We performed exome sequencing in the two siblings with aborted cardiac arrest. This identified 75 novel heterozygous non-synonymous and splice site substitutions that were shared among the two siblings and which were not present in any of the publicly available variant databases. We subsequently overlayed these variants with a comprehensive list of cardiac candidate genes and identified a missense mutation affecting a highly conserved amino acid in the CALM1 gene (p. Phe90Leu) encoding calmodulin. This variant was absent in 100 individuals of Moroccan descent. The mutation was inherited from the asymptomatic mother who displayed a somewhat prolonged QT-interval. DNA was available for one of the two sibs who had died suddenly; this individual also carried the p. Phe90Leu mutation in CALM1. Conclusion: We here identified a novel missense mutation in CALM1 associated with exercise-induced QT prolongation, ventricular tachycardia and sudden cardiac death in childhood.