Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare 
arrhythmogenic disorder characterized by syncopal events and sudden cardiac 
death at a young age during physical stress or emotion, in the absence of 
structural heart disease. We report the first nonsense mutations in the cardiac 
calsequestrin gene, CASQ2, in three CPVT families. The three mutations, a 
nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to 
induce premature stop codons. Two patients who experienced syncopes before the 
age of 7 years were homozygous carriers, suggesting a complete absence of 
calsequestrin 2. One patient was heterozygous for the stop codon and experienced 
syncopes from the age of 11 years. Despite the different mutations, there is 
little phenotypic variation of CPVT for the CASQ2 mutations. Of the 16 
heterozygous carriers of these various mutations, 14 were devoid of clinical 
symptoms or ECG anomalies, whereas 2 of them had ventricular arrhythmias at ECG 
on exercise tests. In line with this, the diagnosis of the probands was 
difficult because of the absence of a positive family history. In conclusion, 
these additional three CASQ2 CPVT families suggest that CASQ2 mutations are more 
common than previously thought and produce a severe form of CPVT. The full text 
of this article is available at http://www.circresaha.org.