RYR2 – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable myocardial disease characterized by fibrofatty replacement of the right ventricular free wall and life-threatening ventricular arrhythmias. A subtype, ARVC type 2 (ARVD2), maps to chromosome 1q42–q43 and is caused by point mutations in the cardiac ryanodine receptor gene RYR2, encoding the sarcoplasmic reticulum Ca2+ release channel.

1. Clinical Validity

Genetic studies have identified RYR2 mutations in a total of 5 unrelated ARVC probands (4 families with ARVD2 [PMID:11159936], 1 postmortem index case with fibrofatty infiltration and sudden death [PMID:16084945]). Segregation of disease with RYR2 variants has been observed in multiple affected relatives (n=4). Concordant functional data from cellular assays and an R420W knock-in mouse model support a pathogenic role. Overall, the evidence meets ClinGen criteria for a Strong gene-disease association.

2. Genetic Evidence

Inheritance follows an autosomal dominant pattern with incomplete penetrance. Four independent ARVD2 families were reported with distinct missense mutations clustering in evolutionarily conserved domains of RyR2 ([PMID:11159936]). An additional index case harboring the c.230C>T (p.Ala77Val) variant was identified in a juvenile sudden death ARVC patient ([PMID:16084945]). All reported pathogenic alleles to date are missense changes affecting channel regulation without loss-of-function truncations.

3. Functional Evidence

Mechanistically, ARVD2 mutations perturb RyR2 gating, leading to diastolic Ca2+ leak and arrhythmogenesis. In vitro studies demonstrate altered channel open probability and FKBP12.6 unbinding in mutant channels. Knock-in mice with the R420W mutation recapitulate juvenile sudden death and histological hallmarks of ARVC, including fibrofatty replacement and myocyte calcium phosphate deposition ([PMID:25087098]).

4. Integration and Conclusion

RYR2-mediated Ca2+ dysregulation underpins ARVC2 pathogenesis, linking genetic and experimental findings. While additional rare variants have been described, current data sufficiently satisfy ClinGen scoring caps. Genetic testing of RYR2 should be considered in ARVC patients lacking desmosomal gene mutations, enabling early diagnosis and cascade screening.

Key Take-home: RYR2 mutations cause a dominant ARVC subtype via a gain-of-function Ca2+ leak mechanism, informing molecular diagnosis and family risk stratification.

References

• Human molecular genetics • 2001 • Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) PMID:11159936
• Human pathology • 2005 • Juvenile sudden death in a family with polymorphic ventricular arrhythmias caused by a novel RyR2 gene mutation: evidence of specific morphological substrates. PMID:16084945
• Legal medicine (Tokyo, Japan) • 2014 • Hypertrophy of lymphoid organs is a possible phenotypic characteristic of R420W mutation of the cardiac ryanodine receptor gene: a study using a knock-in mouse model. PMID:25087098

Evidence Based Scoring (AI generated)