Catecholaminergic Polymorphic Ventricular Tachycardia in the Young: An Analysis of Genetic Data From an International, Multicentre Registry

Advances in the diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia

“…The PACES CPVT Registry has also suggested an association between life-threatening events and mutations in specific regions of RyR2. 23 In this paediatric population, all intersubunit interface variants of hotspot 1 led to cardiac arrest, and cardiac arrest seems to frequently occur in patients with mutations at the S4-S5 linker and helices S5 and S6 of the C-terminus. 23 Collectively, these data support the existence of genotypic and arrhythmic predictors of cardiac events, however, larger studies of unselected populations are needed before these prognosticators can be used to inform therapeutic decisions.…”

“…22 On the basis of existing studies, it is impossible to calculate the true rate of de novo variants because of the prevalence of incomplete parental screening. 23 Calsequestrin (CASQ2) is a protein that interacts with RyR2. 18 Mutations in the gene that encodes CASQ2 underly CPVT2, a highly lethal form of CPVT, and is inherited in an autosomal-recessive manner.…”

“…24 A mild arrhythmia phenotype may also occur in heterozygous carriers of CASQ2 variants. 26,27,23 Further studies are needed to verify the existence of this form of CPVT2 and to determine arrhythmic risk in heterozygous carriers.…”

“…A pathogenic mutation in a gene known to underlie CPVT can confirm a diagnosis; 10 however, pathogenicity is often unclear, 23 and despite standard molecular analysis, and more recently whole-exome sequencing, up to half of cases have no known genetic cause. 3,4,23 Other proteins and molecules known to interact with RyR2for example, ankyrin-B, triadin, junctin, calmodulin, and voltagegated sodium channel Vare implicated in the condition, although current knowledge is limited to case reports or small series. [28][29][30][31][32] Basic and translational studies are underway to understand the newly discovered phenomenon of loss-of-function RyR2 mutations.…”

“…4,12,21 The difficulty in predicting phenotype on the basis of genotype alone is likely influenced by a variety of factors, including incomplete familial penetrance, unidentified genetic modifiers, and a limited knowledge of pathogenicity for many novel mutations. 12,23,59 A greatest challenge is the poor predictive value of exercise testing. In one large family of >1000 relatives, the initial exercise test was normal in 72% of mutation-positive patients.…”