LAUSR

Mitral valve prolapse (MVP) is largely considered a benign condition. Recently, arrhythmogenic MVP, a sudden cardiac death (SCD)-predisposing condition characterized clinically by frequent/complex ventricular arrhythmias likely secondary to prolapsing leaflet-induced fibrosis of the left ventricle (LV), has emerged as an underappreciated cause of sudden unexplained death in the young (SUDY). To determine the prevalence and potential genetic underpinnings of suspected arrhythmogenic MVP in a referral cohort of SUDY cases. In this retrospective necropsy study, the medical records, autopsy reports, and whole exome molecular autopsy (WEMA) results for 77 SUDY victims (27 females; average age at death 20.6±8.9 years) were reviewed. Evidence of myxomatous MVP and concomitant LV pathology were noted. Variants detected in the pre-specified 164 WEMA gene panel with a frequency <0.001 in public exomes were classified using the 2015 American College of Medical Genetics (ACMG) guidelines. Overall, 6/77 (7.8%; 2 females; average age at death 20.7±6.9 years) SUDY cases had MVP as the lone abnormal post-mortem finding. The majority had bileaflet involvement (5/6; 83%) and microscopic LV fibrosis (5/6; 83%). Two SUDY cases (33%) were diagnosed with MVP by echocardiography prior to death. No gross hypertrophy, myocyte disarray, or fibrofatty replacement was noted. Unexpectedly, an ACMG pathogenic/likely pathogenic (P/LP) was more likely to be detected in SUDY cases with MVP than those without [3/6 (50%) vs 9/71 (13%); p<0.05]. Interestingly, the three 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). This WEMA series provides additional evidence that the combination of bileaflet MVP and microscopic LV fibrosis underlies an unexpected number of SUDY cases. Whether P/LP variants in cardiomyopathy/channelopathy-susceptibility genes function as contributing factors or if unrelated, but poorly understood, molecular mechanisms account for the distinct cardiomyopathy-like phenotype observed in arrhythmogenic MVP requires further investigation.