Whole-genome sequencing in mitral valve prolapse – an exploratory study on genes associated with mitral valve prolapse and cardiac arrhythmias
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Background
Mitral valve prolapse (MVP) is a leading cause of mitral regurgitation in high-income countries. Although the course of MVP is often benign, a subset of patients progresses to significant valvular insufficiency, and a smaller subset develops ventricular arrhythmias or sudden cardiac death. This study aimed to identify genetic variants associated with MVP and/or mitral annulus disjunction (MAD) using whole-genome sequencing (WGS) in a Norwegian cohort.
Methods
WGS was performed in 93 individuals diagnosed with MVP and/or MAD, of whom 92 passed genomic quality control criteria. Variants were called using Genome Analysis ToolKit (GATK) Best Practices and compared with non-Finnish European reference data from gnomAD (n = 34 029). Analyses were restricted to curated gene panels comprising: (i) non-syndromic MVP and cardiomyopathy genes, (ii) syndromic/connective tissue disorder genes, and (iii) arrhythmia-related genes. Enriched or underrepresented variants were identified using Fisher’s exact test with Bonferroni correction for multiple testing. Independent variants were derived through linkage disequilibrium pruning. A sensitivity analysis was conducted using low-coverage WGS data from an independent large Norwegian cohort – the Trøndelag Health Study (HUNT).
Results
Across predefined gene panels, several coding and regulatory variants were significantly associated with MVP and/or MAD. A missense variant in FLNA and regulatory variants in TBX5 and SMAD4 were enriched in these patients. Additional significant associations involved regulatory variants in XYLT1, HS3ST4, SH3PXD2B , and a synonymous variant in COL1A2 . Furthermore, several regulatory variants in arrhythmia-related genes ( KCNK3, CACNA1D, NR2F1, KCNJ4 and others) were identified. Sensitivity analyses revealed population-level differences, underscoring the need of cautious interpretation of these findings.
Conclusion
This targeted WGS study expands the genetic landscape of MVP and/or MAD, identifying several coding and regulatory variants across extracellular matrix, developmental, and electrophysiological pathways. These results support a multifactorial genetic architecture of MVP.
Graphical Abstract
Whole-genome sequencing of 92 Norwegian patients with mitral valve prolapse (MVP) and/or mitral annulus disjunction (MAD) identified coding and regulatory genetic variants across three curated gene categories: (i) non-syndromic MVP/cardiomyopathy genes, (ii) syndromic MVP/connective tissue disorder genes, and (iii) arrhythmia-related genes. Key associations included variants in FLNA, TBX5, COL1A2, SMAD4 , and several electrophysiological genes including KCNK3, CACNA1D, NR2F1 , and KCNJ4 . The findings implicate extracellular matrix (ECM) remodeling, transforming growth factor-β (TGF-β) signaling, cardiac developmental pathways, cytoskeletal integrity, and electrophysiological mechanisms, supporting a multifactorial genetic architecture of MVP/MAD.
