{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:23:12Z","timestamp":1768566192382,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,17]]},"group-title":"Cardiovascular Medicine","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Isolated 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    We 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. Functional\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    investigations were performed in zebrafishand in Hek293T cells.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    In 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 in\n                    <jats:italic>ARHGAP24. ARHGAP24<\/jats:italic>\n                    encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation.\n                    <jats:italic>In vitro<\/jats:italic>\n                    functional studies showed that variants of FilGAP, found in PostMVP families, are\n                    <jats:italic>loss-of-function<\/jats:italic>\n                    variants impairing cellular adhesion and mechano-transduction capacities.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>\n                    PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of\n                    <jats:italic>loss-of-function<\/jats:italic>\n                    variants in\n                    <jats:italic>ARHGAP24<\/jats:italic>\n                    further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CLINICAL PERSPECTIVE<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic trait<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>PostMVP has both genetic and functional pathophysiological origins<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Genetic variants in the\n                        <jats:italic>ARHGAP24<\/jats:italic>\n                        gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2024.10.16.24315096","type":"posted-content","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T03:45:12Z","timestamp":1729223112000},"source":"Crossref","is-referenced-by-count":0,"title":["Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic 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