Whole-genome sequencing in mitral valve prolapse: an exploratory study on genes associated with mitral valve prolapse and cardiac arrhythmias

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 Trondelag 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.