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Published on: May 19, 2020
Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology
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 traitPostMVP 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.
Insights
Isolated posterior mitral valve prolapse (PostMVP) is an inherited condition, not just degenerative. Genetic variants in ARHGAP24 impair cell adhesion and mechano-transduction, causing familial PostMVP.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Biomedical Research
Background:
- Isolated posterior mitral valve prolapse (PostMVP), also known as fibro-elastic deficiency, is typically viewed as a degenerative condition.
- Patients are often asymptomatic until chordal rupture, leading to delayed diagnosis.
- This study investigates the familial characteristics, genetic basis, and pathophysiology of PostMVP.
Purpose of the Study:
- To characterize the familial phenotype and recurrence of PostMVP.
- To identify the genetic background of inherited PostMVP.
- To elucidate the pathophysiological mechanisms underlying PostMVP.
Main Methods:
- Prospective enrollment of 284 mitral valve prolapse (MVP) probands, with detailed phenotyping.
- Familial screening of 106 PostMVP patients identified 20 families for whole-genome sequencing.
- Functional studies using zebrafish and Hek293T cells were conducted.
Main Results:
- In 20 families, 38.8% of relatives exhibited MVP, primarily posterior leaflet, suggesting autosomal dominant inheritance.
- PostMVP patients showed distinct posterior leaflet dystrophy on echocardiography compared to controls.
- Rare variants in ARHGAP24, encoding FilGAP, were identified; loss-of-function variants impaired cellular adhesion and mechano-transduction.
Conclusions:
- PostMVP is a heritable phenotypic trait with genetic and functional origins, not solely degenerative.
- Loss-of-function variants in ARHGAP24 highlight the role of mechano-transduction pathways in MVP pathogenesis.
- ARHGAP24 variants impair cell adhesion and mechano-transduction, contributing to familial PostMVP progression.
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