A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence.
OBJECTIVE
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.
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
Roos F
RF
Marsman
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands; ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
Julien
J
Barc
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
Leander
L
Beekman
Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
Marielle
M
Alders
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Dennis
D
Dooijes
Department of Clinical Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands.
Arthur
A
van den Wijngaard
Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohamed V Souissi, Rabat, Morocco.
Ilham
I
Ratbi
Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohamed V Souissi, Rabat, Morocco.
Abdelaziz
A
Sefiani
Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands; Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Zahurul A
ZA
Bhuiyan
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands; Princess Al Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
Arthur A M
AA
Wilde
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.r.bezzina@amc.uva.nl.
Connie R
CR
Bezzina
D000293:Adolescent; D002147:Calmodulin / Q000235:genetics*; D002648:Child; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
D002147:Calmodulin; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D004247:DNA
CPVT; CaM; DNA; ECG; ICD; IVF; LQTS; OHCA; calmodulin; catecholaminergic polymorphic ventricular tachycardia; deoxyribonucleic acid; electrocardiogram/electrocardiographic; exome sequencing; genetics; idiopathic ventricular fibrillation; idiopathic ventricular fibrillation; implantable cardioverter-defibrillator; long-QT syndrome; out-of-hospital cardiac arrest; ventricular arrhythmia