• Roos F Marsman, Julien Barc, Leander Beekman, Marielle Alders, Dennis Dooijes, Arthur van den Wijngaard, Ilham Ratbi, Abdelaziz Sefiani, Zahurul A Bhuiyan, Arthur A M Wilde, and Connie R Bezzina.
• Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
• J. Am. Coll. Cardiol. 2014 Jan 28; 63 (3): 259-66.

ObjectivesThis study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence.BackgroundAlthough sudden cardiac death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities.MethodsExome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest.ResultsWe characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise.ConclusionsWe identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals.Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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