Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1.

Abstract

Human cardiac <i>ryanodine receptor 2</i> (<i>RYR2</i>) shows autosomal-dominant inheritance in catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1); however, <i>de novo</i> variants have been observed in sporadic cases. Here, we investigated CPVT1-related <i>RYR2</i> variant inheritance and its clinical significance between familial and <i>de novo</i> cases. We enrolled 82 independent CPVT1 probands (median age: 10.0 (7.0-13.0) years; 45 male) carrying the <i>RYR2</i> variants and whose biological origin could be confirmed by parental genetic analysis: assured familial inheritance (familial group: n=24) and <i>de novo</i> variants (<i>de novo</i> group: n=58). We examined the clinical characteristics of the probands and their family members carrying the <i>RYR2</i> variants. In the <i>de novo</i> group, the <i>RYR2</i> variants were more likely located in the C-terminus domain and less likely in the N-terminus domain than those in the familial group. The cumulative incidence of the first cardiac events (syncope and cardiac arrest (CA) or CA only) of the probands at the age of 5 and 10 years was higher in the <i>de novo</i> group than in the familial group. Nearly half of the probands in both groups experienced CA events before diagnosis. Only 37.5% of their genotype-positive parents had symptoms; however, at least 66.7% of the genotype-positive siblings were symptomatic. CPVT1 probands harbouring <i>de novo RYR2</i> variants showed an earlier onset of symptoms than those with assured familial inheritance. Cascade screening may enable early diagnosis, risk stratification and prophylactic therapeutic intervention to prevent sudden cardiac death of probands and potential genotype-positive family members.