Abstract 4147050: Genetic Insights into Arrhythmogenic Mitral Valve Prolapse – A Case-Control Study from UK Biobank and NIH All of Us

Mitral valve prolapse (MVP) is a common valvular abnormality. Observational studies demonstrate an association between MVP and increased risk of sudden cardiac death from ventricular arrhythmias, coined arrhythmogenic MVP. A genetic component has been postulated but remains under-investigated. Predicted deleterious variants in Mendelian cardiomyopathy and arrhythmia genes are more frequent in arrhythmogenic MVP (aMVP) compared to non-arrhythmogenic MVP. To comprehensively phenotype and genotype a single-center cohort and compare to from two large population-based cohorts and investigate their clinical outcomes. The cohort included 46 prospectively enrolled patients from a regional referral center for inherited cardiovascular disease and had undergone multi-modality imaging and clinical gene panel testing. The comparator cohorts included 453 participants from the UK Biobank (UKBB), a prospective cohort of 500,000 UK residents, and 1,418 participants from the National Institutes of Health (NIH) All of Us (AoU), a prospective cohort of 450,000 USA participants. Gene variants were annotated in ANNOVAR. Participants with and without pathogenic/likely pathogenic (P/LP) variants reported on ClinVar with ≥2-star level of evidence were considered genotype positive (G+) and negative (G-) respectively. The demographics for (age 61.2 ± 12.8 years, 56.5% female) and (UKBB: age 59.8 ± 7.3 years, 50.7% female and AoU: age 65.3 ± 13.4 years, 76.2% female) were comparable. G+ participants were more prevalent in the cohort 10/46 (21.7%) versus in the UKBB 8/453 (1.8%) and in the AoU 21/1418 (1.5%); p<0.001. The most frequently implicated gene in was . Of 46 in cohort, 33 (71%) underwent CMR. G+ participants had a higher frequency of late gadolinium enhancement [6/6 (100%) vs. 14/27 (51.8%), p<0.001] and wall motion abnormalities [3/6 (50%) vs. 1/27 (3.7%), p<0.001] compared to G- participants. The cohort had significantly more implantable cardioverter defibrillator (ICD) implants compared to cohort [5/46 (10.9%) vs. 1/453 in UKBB (0.2%), p<0.001]. G+ cohort showed a trend for developing heart failure and ICD implants compared to G- . P/LP variants in cardiomyopathy and arrhythmia genes are more prevalent in participants compared to participants. This could be a hitherto unrecognized effect modifier predicting .

Duke Scholars

Author Andrew Paul Landstrom Pediatrics, Cardiology