Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology

Year: 2024

Type: preprint

Abstract: ABSTRACT BACKGROUND 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. METHODS 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 in vivo and in vitro investigations were performed in zebrafishand in Hek293T cells. RESULTS 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 ARHGAP24. ARHGAP24 encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation. In vitro functional studies showed that variants of FilGAP, found in PostMVP families, are loss-of-function variants impairing cellular adhesion and mechano-transduction capacities. CONCLUSIONS 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 loss-of-function variants in ARHGAP24 further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP. CLINICAL PERSPECTIVE Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic trait PostMVP has both genetic and functional pathophysiological origins Genetic variants in the ARHGAP24 gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities

Source: medRxiv

DOI: 10.1101/2024.10.16.24315096

Institutions: Centre National de la Recherche Scientifique, Inserm, Centre Hospitalier Universitaire de Nantes, Institut du Thorax, Nantes Université, Centre Hospitalier Universitaire d'Angers, Universitat Pompeu Fabra, Hospital Del Mar, Centre for Genomic Regulation, Hospital del Mar Research Institute, Masonic Medical Research Laboratory, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Laboratoire Traitement du Signal et de l'Image, CIC Rennes, Centre Hospitalier Universitaire de Rennes, Université Rennes 1, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay - Etablissement de Saclay, Centre National de Recherche en Génomique Humaine, Centro de Investigación Biomédica en Red, Municipal Institute for Medical Research, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Massachusetts General Hospital, Medical University of South Carolina, Hôpital Pontchaillou, Université Paris Cité, Paris Cardiovascular Research Center, Fondation Leducq

Language: English

Topic: Cardiac Valve Diseases and Treatments

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Science Foundation, American Heart Association, Medical University of South Carolina, Infrastructures en Biologie Santé et Agronomie, Institut Français de Bioinformatique, European Commission, Agence Nationale de la Recherche, Fondation Leducq, Fondation pour la Recherche Médicale, Fédération Française de Cardiologie, Société Française de Cardiologie, Conseil Régional des Pays de la Loire, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Center for Research Resources

Awards: Mitral Valve Disease: From Genetic Mechanisms to Improved Repair, Mechanosensing and Mitral Valve Prolapse: from the Molecular Mechanisms to the Progression of the Disease, G2558356852, G2579310621, Genetics and Mechanisms of Mitral Valve Prolapse, G3424230964, G3444564074, G350062807, MItral Valve Disease: From Genetics to Mechanisms and Improved CARE, G381665449, 2009 Research Infrastructure Improvement Grant, G434337789, G5103928679, G5168622289, G5239235424, G5305657220, G5690318517, G5710227431, G5743453972, G5802621812, Institut français de bioinformatique, EXTRAMURAL RESEARCH FACILITIES CONSTRUCTION, G6516395363, G6808172883, G7174040545, G7240651115, Bioengineering Center of Regeneration and Formation of Tissues (SC BioCRAFT), Improving Mitral Compensation in Ischemic Regurgitation, Dzip1 and Mitral Valve Prolapse, G7999552054, G8469130213, G8498956599, G9000054258, G9000135001, G9000210174, Cilia and Valvular Heart Disease

OpenAlex ID: W4403550635