Prevalence and potential genetic determinants of young sudden unexplained death victims with suspected arrhythmogenic mitral valve prolapse syndrome
John R. Giudicessi, Joseph J. Maleszewski, David J. Tester, Michael J. Ackerman
Abstract
BACKGROUND: Mitral valve prolapse (MVP) is largely considered a benign condition. However, MVP is over-represented consistently in sudden unexplained death in the young (SUDY) cohorts. OBJECTIVE: To determine the prevalence and potential genetic underpinnings of suspected arrhythmogenic MVP in a referral cohort of SUDY cases. METHODS: In this retrospective study, medical records/autopsy reports and whole exome molecular autopsy (WEMA) results for 77 SUDY victims (27 female; average age at death 20.6 ± 8.9 years) were reviewed for evidence of myxomatous MVP and left ventricle (LV) fibrosis. Variants detected in the prespecified 147 WEMA gene panel with a minor allele frequency ≤ 0.001 in public exomes/genomes were classified using the 2015 American College of Medical Genetics (ACMG) guidelines. RESULTS: < .05). Interestingly, the 3 variants identified in MVP-positive SUDY cases localized to genes associated previously with a cardiomyopathy/channelopathy predisposition (p.E1518fsX25-DMD, p.S285N-RYR2, and p.R109X-TTN). CONCLUSION: This WEMA series provides additional evidence that the combination of MVP and LV fibrosis underlies an unexpected number of SUDY cases. Whether P/LP variants in cardiomyopathy/channelopathy-susceptibility genes contribute to the pathogenesis of arrhythmogenic MVP requires further investigation.