PROJECT SUMMARY Mitral valve prolapse (MVP) is a common valvulopathy with a strong hereditary component affecting over 7 million individuals in the United States. Every year, up to 1.8% of MVPs will develop sudden cardiac arrest (SCA) or sudden cardiac death (SCD). In prior studies, SCD/SCA in MVP has either been linked to severe mitral regurgitation (MR) or to a malignant bileaflet phenotype with mild MR, mitral annular disjunction (MAD) and abnormal valvular-myocardial mechanics leading to complex ventricular ectopy (ComVE) and/or left ventricular replacement fibrosis [late gadolinium enhancement or LGE by cardiac magnetic resonance (CMR) imaging]. We have shown, supported by an ongoing R01, that diffuse fibrosis by CMR/T1 mapping is linked to increased arrhythmic risk, regardless of bileaflet phenotype, severe MR, or presence of LGE. Hence, arrhythmic MVP may not be a “pure” valvulopathy, but rather a component of a primary subclinical myopathy. In addition to mutations in cilia-related genes (DCHS1, TNS1, LMCD1, DZIP1) previously described in “general” MVP, cardiomyopathy or channelopathy genes (FLNC, LMNA, ALPK3, SCN5A) have been recently proposed in arrhythmic MVP, albeit in case reports, or GWAS studies with heterogeneous presentations. Through an ongoing R01 and an expanding MVP registry at our institution, we have identified a total of 14 arrhythmic MVP probands and pedigrees, and 50 sporadic arrhythmic MVP cases. In this administrative supplement application, we seek to complete whole exome sequencing, arrhythmic characterization, and CMR in a minority of family members that have yet to undergo these investigations. Our central hypothesis is that among MVP genetic variants, cardiomyopathy or channelopathy genes act alone or in combination with cilia- related variants to increase the risk of SCD/SCA in MVP. To test our central hypothesis and accomplish our overall objective, we propose the following Specific Aims: Aim 1: To identify clinical features and genetic determinants of arrhythmic risk in MVP SCD/SCA pedigrees, and Aim 2: To test pathogenicity of genetic variants and understand mechanisms of arrhythmic MVP using protein expression data and cell model assays. Data obtained through this administrative supplement is essential for better MVP SCD/SCA risk stratification, thus enabling future prevention of SCD via ICD placement in appropriately selected MVP patients. Use of cell model assays to validate our genetic findings is essential to understand arrhythmogenesis in MVP patients. Our proposal is motivated by a recent NHLBI workshop on research opportunities in MVP and the CAROL Act in memory of a US congressman’s wife who died suddenly from MVP.