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

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Abstract 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 – 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 – 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. Clinical Perspective What Is Known Cardiomyopathy/channelopathy gene variants have been linked to sudden cardiac arrest or death in small, selected pedigree or post-mortem studies of arrhythmic mitral valve prolapse (MVP). Imaging studies have highlighted a diffuse myopathic process in patients with arrhythmic MVP and their family members. What The Study Adds In consecutive MVP patients, cardiomyopathy/channelopathy genetic mutations are linked to a subclinical myopathy by strain echocardiography and a greater risk for severe ventricular arrhythmias independently of bileaflet involvement and mitral annular disjunction A clinical whole exome sequencing panel inclusive of cardiomyopathy/channelopathy genetic variants may represent a valuable arrhythmic risk stratification tool in MVP beyond traditional imaging parameters Abstract Figure Graphical Abstract: Cardiomyopathy/Channelopathy Genetic Testing in Mitral Valve Prolapse. Genetic samples from 203 MVPs were sequenced, and MVPs were subsequently divided based on whether they carried P/LP variants in CC genes (Top Left) or not. P/LP variants were identified in multiple genes associated with a variety of CC conditions (Bottom Left). A Kaplan-Meier curve demonstrates that P/LP variant carriers are at higher risk for the composite arrhythmic outcome beginning at birth (Right).

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