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

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.