RYR2 – Catecholaminergic Polymorphic Ventricular Tachycardia type 1

Autosomal‐dominant variants in the cardiac ryanodine receptor gene RYR2 have been firmly established as the primary genetic cause of catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1). Extensive case series and family‐based studies over the past two decades have identified over 100 unrelated probands harboring heterozygous RYR2 missense mutations clustering in three hot‐spot regions (PMID:11807805; PMID:11159936). Sympathetic stimulation–mediated protein kinase A phosphorylation of mutant RyR2 leads to destabilization of FKBP12.6 binding, diastolic SR Ca2+ leak, and delayed afterdepolarizations underlying exercise‐induced ventricular arrhythmias.

In a recent cascade‐screening cohort of 82 independent CPVT1 probands (median age 10 years), de novo RYR2 variants accounted for 71% of cases, with the remainder showing familial inheritance (PMID:35135837). Familial kindreds demonstrate clear segregation of pathogenic alleles with syncope and cardiac arrest in at least 19 affected relatives. Asymptomatic carriers exhibit low penetrance on exercise testing but remain at risk for sudden death without prophylactic β‐blockade.

Over 60 distinct RYR2 missense substitutions have been reported, spanning N‐ and C‐terminal domains and transmembrane segments. A representative pathogenic variant is c.527G>A (p.Arg176Gln), located within the N‐terminal regulatory region and shown to alter Ca2+‐dependent inhibition and channel gating (PMID:15845383). ClinGen scoring yields a Definitive gene–disease association based on large proband numbers, multi‐family segregation, and consistent mechanistic insights.

Functional characterization in recombinant expression systems, knock‐in mouse models, and patient myocytes show a gain‐of‐function mechanism: mutant RyR2 channels exhibit lowered activation thresholds, enhanced luminal Ca2+‐dependent activation, and PKA‐sensitized Ca2+ release, all consistent with arrhythmogenesis (PMID:15197150; PMID:16339485). Rescue of channel leak with stabilizing compounds such as JTV519 further confirms the pathogenic mechanism and highlights therapeutic opportunities.

No conflicting evidence has emerged disputing RYR2’s role in CPVT1. While rare deep‐intronic or hypomorphic alleles remain under investigation, the current body of genetic and functional evidence achieves the maximum ClinGen classification for a monogenic arrhythmia syndrome.

Key Take-home: Heterozygous RYR2 missense mutations cause CPVT1 via adrenergically triggered diastolic Ca2+ leak, supporting genetic diagnosis, family screening, and targeted β‐blocker or RyR2 stabilizer therapy.

References

• Heart (British Cardiac Society) • 2022 • Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1 PMID:35135837
• Journal of the American College of Cardiology • 2002 • Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers PMID:12106942
• Journal of Medical Genetics • 2005 • Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients PMID:16272262
• Circulation • 2004 • Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak PMID:15197150
• Circulation Research • 2006 • Arrhythmogenic mutation-linked defects in ryanodine receptor autoregulation reveal a novel mechanism of Ca2+ release channel dysfunction PMID:16339485

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