Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology
Authors: Rimbert Antoine , Duval Damien , Trujillano Daniel , Kyndt Florence , Jobbe-Duval Antoine , Lindenbaum Pierre , Tucker Nathan , Lecointe Simon , Labbé Pauline , Toquet Claire , Karakachoff Matilde , Roussel Jean-Christian , Baufreton Christophe , Bruneval Patrick , Cueff Caroline , Donal Erwan , Redon Richard , Olaso Robert , Boland Anne , Deleuze Jean-François ,   FranceGenRef Consortium, Estivill Xavier , Slaugenhaupt Susan , Markwald Roger R , Norris Russel A , Verhoye Jean-Philippe , Probst Vincent , Hagège Albert , Levine Robert , Jeunemaitre Xavier , Marec Hervé Le , Capoulade Romain , Bouatia-Naji Nabila , Dina Christian , Milan David , Ossowski Stephan , Schott Jean-Jacques , Mérot Jean , Scouarnec Solena Le , Tourneau Thierry Le 
Published: October 2024

ABSTRACTBACKGROUNDIsolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved.METHODSWe prospectively enrolled 284 unrelated MVP probands, of whom 178 (63%) had bi-leaflet MVP and 106 had PostMVP (37%). Familial screening within PostMVP patients allowed the identification of 20 families with inherited forms of PostMVP for whom whole genome sequencing was carried out in probands. Functionalin vivoandin vitroinvestigations were performed in zebrafishand in Hek293T cells.RESULTSIn the 20 families with inherited form of PostMVP, 38.8% of relatives had a MVP/prodromal form, mainly of the posterior leaflet, with transmission consistent with an autosomal dominant mode of inheritance. Compared with control relatives, PostMVP family patients have clear posterior leaflet dystrophy on echocardiography. Patients with PostMVP present a burden of rare genetic variants inARHGAP24. ARHGAP24encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation.In vitrofunctional studies showed that variants of FilGAP, found in PostMVP families, areloss-of-functionvariants impairing cellular adhesion and mechano-transduction capacities.CONCLUSIONSPostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification ofloss-of-functionvariants inARHGAP24further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP.CLINICAL PERSPECTIVEIsolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic traitPostMVP has both genetic and functional pathophysiological originsGenetic variants in theARHGAP24gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities