Overview
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy, often caused by pathogenic or likely pathogenic (P/LP) variants in genes encoding sarcomere proteins 1. Not all subclinical variant carriers will manifest clinically overt disease, as penetrance is variable and age-dependent 1. Variants in JPH2 are also associated with a range of cardiac diseases, including HCM, dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD) 2.Diagnosis
Sarcomere P/LP variants are identified in 34% of patients diagnosed with HCM in family/clinical studies 1.
The penetrance of sarcomere P/LP variants in nonproband relatives identified during cascade screening is 57% (95% CI, 52%-63%), with a mean age at HCM diagnosis of 38 years (95% CI, 36%-40%) 1.
Penetrance of sarcomere P/LP variants is highly variable, ranging from approximately 32% for some variants 1.
Among individuals with JPH2* variants, approximately 80% have some form of cardiac disease, including 47% with HCM, 18% with DCM, and 14% with arrhythmia/SCD 2.
Autosomal dominant missense JPH2* variants are associated with HCM, arrhythmia, SCD, and cardiac conduction disease 2.
Autosomal recessive, loss-of-function JPH2* variants are associated with severe, early-onset DCM 2.Special Populations
Autosomal recessive, loss-of-function JPH2* variants are associated with severe, early-onset dilated cardiomyopathy (DCM) 2.Key Recommendations
Genetic testing for sarcomere P/LP variants should be considered in patients with HCM, given their prevalence and penetrance in affected families 1. (Evidence: Moderate)
When interpreting JPH2 variant findings, consider the mode of inheritance and variant type, as autosomal dominant missense variants are linked to HCM, while autosomal recessive loss-of-function variants are associated with severe, early-onset DCM 2. (Evidence: Weak)References
1 Topriceanu CC, Pereira AC, Moon JC, Captur G, Ho CY. Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy. Circulation 2024. link
2 Parker LE, Kramer RJ, Kaplan S, Landstrom AP. One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2. Trends in cardiovascular medicine 2023. link