Abstract Body (Do not enter title and authors here): Introduction:
Mitral valve prolapse (MVP) is a common valvular disorder associated, in a minority of cases, with severe arrhythmic events including sudden cardiac arrest/death (SCA/SCD). Traditional imaging parameters of arrhythmic risk such as bileaflet prolapse, mitral annular disjunction (MAD), and late gadolinium enhancement by cardiac MRI are not found in all SCA survivors, suggesting an alternative arrhythmogenic mechanism. Recently, the presence of a genetic myopathy and/or channelopathy has been suggested in MVP, albeit only in case reports or cross-sectional investigations. Hence, the utility of genetic testing in MVP remains uncertain.

Hypothesis:
Testing for cardiomyopathy/channelopathy (CC) variants in a large MVP cohort will identify a subset with pathogenic/likely pathogenic (P/LP) variants associated with an increased risk of severe arrhythmic events longitudinally.

Methods:
We prospectively recruited MVPs at the University of California, San Francisco between 2017 and 2024. 196/220 patients underwent whole exome sequencing. Variants of interest were rare (<0.1% frequency), protein-coding, nonsynonymous variants in genes present on a selected clinical Arrhythmia and Cardiomyopathy panel. P/LP classification was assigned with an automated algorithm (Franklin). Severe arrhythmic events were defined as SCA/SCD or sustained ventricular arrhythmias requiring an implantable cardioverter defibrillator (ICD) or ablation. We assessed the risk of severe arrhythmic outcomes in MVPs with and without CC P/LP variants using both adjusted logistic regression and survival analyses.

Results:
We included 196 MVPs, of which 187 (95%) had CC variants and 20 (10%) were P/LP (Figure 1). None of the MVPs in our study demonstrated channelopathy or overt cardiomyopathy. However, P/LP variants were significantly associated with severe arrhythmic events after adjusting for age, sex, bileaflet involvement, and MAD (Odds Ratio: 3.1, p=0.03). Time to event analysis confirmed that MVPs with P/LP variants were at significantly increased risk for severe arrhythmic events starting at birth (Figure 2).

Conclusions:
Occult P/LP variants associated with cardiomyopathy or channelopathy independently increase the risk of severe arrhythmic events in MVP. Genetic testing should be investigated as a novel arrhythmic risk stratification tool for MVP, especially for cases that may not yet demonstrate an arrhythmic phenotype but may need closer clinical follow-up.