Utility of genetic screening for the prediction of severe arrhythmic outcomes in mitral valve prolapse

Background: Cardiomyopathy and channelopathy (CC) gene variants have been linked to sudden cardiac arrest (SCA) or death (SCD) in small, selected pedigree or post-mortem studies of arrhythmic mitral valve prolapse (MVP). However, the utility of clinical whole exome sequencing (WES) panels as a risk stratification tool in unselected MVP samples is unknown. Objectives: The goal of the study was to test the utility of clinical WES panels with CC variant screening for arrhythmic risk stratification in MVP. Methods: We performed research based WES in 203 consecutive MVPs without other arrhythmic substrate. Variants were filtered for rare (<0.1%) and protein altering variants in 157 CC genes within an existing clinical panel and annotated with a clinical significance predictor. Overall frequency of CC variants was compared to a sample of general population exomes from gnomad v4.1.0. We assessed a composite severe arrhythmic outcome of SCD or frequent ectopy/ventricular tachycardia or ventricular fibrillation/SCA requiring catheter ablation or defibrillator implantation, respectively. Results: CC variants were more common in MVPs compared to the general population (RR: 4.3, p < 0.01). Pathogenic/Likely Pathogenic (P/LP) variants were identified in 18 MVPs (9%; 8 CC variants among 12 genes). P/LP variants were independently associated with the composite arrhythmic outcome after adjustment for traditional imaging parameters of risk including mitral annular disjunction and bileaflet involvement (OR: 1.23 [95% CI: 1.03 to 1.47], p = 0.01). P/LP variant carriers were at greater arrhythmic risk in time to event analyses starting at birth (HR: 2.87 [95% CI: 1.24 to 6.62], p = 0.01). Conclusions: A subset of MVPs with P/LP variants in CC genes are at higher arrhythmic risk. A clinical WES panel inclusive of CC variants may represent a valuable arrhythmic risk stratification tool in MVP beyond traditional imaging parameters.