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% Cl: 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% Cl: 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.