One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2

Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD); however, our understanding of how variants in JPH2 correspond to specific modes of inheritance and correlate clinical phenotypes has not been comprehensively explored. In this systematic review, we assess current case reports and series that describe patients with JPH2 variants and cardiac disease. We identified a total of 61 variant-positive individuals, approximately 80% of whom had some form of cardiac disease, including 47% HCM, 18% DCM, and 14% arrhythmia/SCD. In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and cardiac conduction disease.

Automated summary

Rare variants in the JPH2 gene are associated with various cardiac diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmias, and sudden cardiac death. This systematic review examines case reports and series describing patients with JPH2 variants and cardiac diseases. A total of 61 individuals with variant-positive were identified, with about 80% having some form of cardiac disease, including HCM, DCM, and arrhythmia/SCD. The analysis of the 24 probands showed that autosomal recessive loss-of-function variants are linked to severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac diseases.