Genetic differences between fibroelastic deficiency and Barlow’s disease in mitral valve prolapse

Abstract Aims Fibroelastic deficiency (FED) and Barlow's disease represent subtypes of degenerative mitral valve prolapse (MVP). Whether these two conditions represent opposite ends of an anatomic spectrum or rather distinct etiologies remains unclear. Methods and Results To study this question from a genetic perspective, we conducted the first genome-wide association study (GWAS) on anatomical subtypes of MVP, exploring the MVP-Munich and MVP-France cohorts, including 1,064 FED and 821 Barlow’s disease cases, and 11,923 controls. Patients were stratified via echocardiographic and surgical reports. GWAS meta-analysis was performed separately for FED and Barlow’s disease. The identified risk loci were analyzed via gene set enrichment analysis (GSEA), targeted variant-phenotype association analysis, and mitral valve tissue was analyzed in single-nucleus RNA-sequencing. For FED, one risk locus achieved genome-wide significance (p<5e-8) at 5q23.3 (CHSY3). For Barlow’s disease, two independent loci with genome-wide significance were identified at 5q35.2 (CPLX2) and 10q26.12 (WDR11). Further 30 additional independent signals showed a suggestive association (p<5e-5) with FED, and 30 different independent signals with Barlow’s disease. Targeted variant-phenotype association analysis revealed an association of FED with atrial arrhythmias, while Barlow’s disease was associated with atrial and ventricular arrhythmias. In combination with GSEA, our results linked Barlow’s disease to changes in cell cycle, transcription, senescence, and ubiquitination. FED was connected to cardiac, valvular, mesoderm, and endoderm development. Conclusions This study suggests genetic heterogeneity between FED and Barlow’s disease and identifies risk loci for future investigation.

Authors

Institutions

Publication Details

Journal
Cardiovascular Research
Published
2026-10-28
DOI
https://doi.org/10.1093/cvr/cvag263
Primary Topic
Cardiac Valve Diseases and Treatments
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Genetic differences between fibroelastic deficiency and Barlow’s disease in mitral valve prolapse

Heribert Schunkert, Mengyao Yu, Nina Feirer, Stefanie A. Doppler et al.
Cardiovascular Research
Cardiac Valve Diseases and Treatments
article

Genetic differences between fibroelastic deficiency and Barlow’s disease in mitral valve prolapse

Heribert Schunkert, Mengyao Yu, Nina Feirer, Stefanie A. Doppler, Katharina Knoll, Martina Dreßen, Teresa Trenkwalder, Bertram Müller‐Myhsok, Harald Lahm, Aeron Small, Albert Alain Hagège, Arnar Geirsson, Peter Lichtner, Monika Stoll, Nabila Bouatia‐Naji, Klaus Berger, Tatjana Luzius, Peter J. Gruber, Marius Schwab, Markus Krane, Lucas Miranda, Ehsan Vafadarnejad, Rüdiger Lange, Irina Gottmann, Muamer Kameric, Ling Li, Sabine Seeler, Melanie Weber, Felix Wirth
article en

Abstract

Abstract Aims Fibroelastic deficiency (FED) and Barlow's disease represent subtypes of degenerative mitral valve prolapse (MVP). Whether these two conditions represent opposite ends of an anatomic spectrum or rather distinct etiologies remains unclear. Methods and Results To study this question from a genetic perspective, we conducted the first genome-wide association study (GWAS) on anatomical subtypes of MVP, exploring the MVP-Munich and MVP-France cohorts, including 1,064 FED and 821 Barlow’s disease cases, and 11,923 controls. Patients were stratified via echocardiographic and surgical reports. GWAS meta-analysis was performed separately for FED and Barlow’s disease. The identified risk loci were analyzed via gene set enrichment analysis (GSEA), targeted variant-phenotype association analysis, and mitral valve tissue was analyzed in single-nucleus RNA-sequencing. For FED, one risk locus achieved genome-wide significance (p<5e-8) at 5q23.3 (CHSY3). For Barlow’s disease, two independent loci with genome-wide significance were identified at 5q35.2 (CPLX2) and 10q26.12 (WDR11). Further 30 additional independent signals showed a suggestive association (p<5e-5) with FED, and 30 different independent signals with Barlow’s disease. Targeted variant-phenotype association analysis revealed an association of FED with atrial arrhythmias, while Barlow’s disease was associated with atrial and ventricular arrhythmias. In combination with GSEA, our results linked Barlow’s disease to changes in cell cycle, transcription, senescence, and ubiquitination. FED was connected to cardiac, valvular, mesoderm, and endoderm development. Conclusions This study suggests genetic heterogeneity between FED and Barlow’s disease and identifies risk loci for future investigation.

Cardiovascular Research
Broad Institute (US), Brigham and Women's Hospital (US), University of Liverpool (GB), Inserm (FR), Université Paris Cité (FR), University of Münster (DE), Fudan University (CN), Helmholtz Zentrum München (DE), Yale University (US), Massachusetts General Hospital (US), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Européen Georges-Pompidou (FR), Institute of Human Genetics (PL), Pudong Medical Center (CN), German Centre for Cardiovascular Research (DE), Paris Cardiovascular Research Center (FR), HolsboerMaschmeyer NeuroChemie (Germany) (DE), Max Planck Institute of Psychiatry (DE), Deutsches Herzzentrum München (DE), Max Planck Institute of Biochemistry (DE), Technical University of Munich (DE), Columbia University (US)
Openalex Percentile: Top 11%
Cardiac Valve Diseases and Treatments
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon