Abstract Body (Do not enter title and authors here): Background: Variants in JPH2-encoded junctophilin 2 have been associated with a range of cardiac diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmias, and sudden cardiac death. Despite these associations, due to its rarity, there is limited understanding of the penetrance and clinical spectrum of disease. Defining the clinical impact of JPH2 variants is essential for enhancing risk assessment, early diagnosis, and guiding clinical management in this rare disease.

Objective: To determine the penetrance and cardiac phenotypic spectrum associated with JPH2-mediated disease.

Methods: An international, multi-center registry of JPH2 variant-positive individuals was developed from participating clinical sites and the literature. Inclusion criteria were 1) a diagnostic JPH2 variant by ACMG criteria (likely pathogenic/pathogenic LP/P) or a variant of uncertain significance (VUS) in JPH2, and 2) at least 1 cardiac evaluation. Exclusion criteria were 1) variant rated likely benign/benign (LB/B) by ACMG and/or 2) presence of a compound rare/diagnostic variant in a known cardiomyopathy-associated gene. Heart failure was defined as LVEF ≤ 40, a clinical diagnosis of heart failure, or a heart transplant.

Results: Fifty-nine cases were identified for this cohort, making it the largest cohort of JPH2-positive cases to date. Of the cohort, 61% were male, 27% were female, and 12% had unknown gender. Among the variants identified, 88% were monoallelic, 10% were biallelic, and 2% had unknown zygosity. Of the monoallelic variants, 6% were loss-of-function (LOF) variants and 94% were missense variants. Within the cohort, 33% of participants with biallelic variants developed HF compared to 12% of those with monoallelic missense variants. Overall, 15% of the participants developed heart failure. Based on ACMG classification, 67% of individuals who developed heart failure had LP/P variants, while 33% had a VUS. In terms of broader cardiac manifestations, participants in this cohort, 76% developed cardiomyopathy, 58% developed arrhythmias, 3% had congenital heart disease, 3% had other types of cardiovascular disease, and 12% had no cardiac manifestations.

Conclusions: JPH2 variants appear to have high penetrance, likely driven by variant type, and primarily manifest as cardiomyopathy and arrhythmias.