OBJECTIVES: This study aimed to identify the genetic defect in a family with 
idiopathic ventricular fibrillation (IVF) manifesting in childhood and 
adolescence.
BACKGROUND: Although 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.
METHODS: Exome sequencing was carried out on 2 family members who were both 
successfully resuscitated from a cardiac arrest.
RESULTS: We 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.
CONCLUSIONS: We 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.