Genetic characterization of familial CPVT after 30 years

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-related, bidirectional ventricular tachycardia and atrial tachyarrhythmia in the absence of either structural heart disease or prolonged QT interval. Autosomal dominant and recessive forms of CPVT because of mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin 2 (CASQ2) have been reported. The objective of this study was the clinical and genetic characterization of the family of an individual initially diagnosed as a child in 1978.

We collected family medical history and recorded a four-generation pedigree. We performed mutation analysis of RyR2 "critical regions'' in the N-terminus, FKBP12.6 binding domain, Ca2+ binding domain, and transmembrane domains of the C-terminus by direct sequencing.

CPVT was diagnosed in two of the nine family members evaluated. Pedigree analysis suggested autosomal dominant disease transmission. There were no additional reports of seizures, pregnancy loss, neonatal death, or sudden cardiac death in family members. A novel RyR2 gene variant (W4645R) was found in four family members including two without symptoms. RyR2-W4645R segregates with disease in this family with incomplete penetrance. The W4645 residue is evolutionarily conserved in the transmembrane region adjacent to previously reported disease-causing mutations. Based on sorting intolerant from tolerant analysis of protein structure, RyR2-W4645R is predicted to be deleterious.

All current evidence supports RyR2-W4645R as a disease-causing variant, which was silent in persons for two generations before causing symptoms in persons for the next two generations, beginning in 1978.