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

BackgroundMitral 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. MethodsWGS 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 Fishers 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). ResultsAcross 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. ConclusionThis 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 AbstractWhole-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-{beta} (TGF-{beta}) signaling, cardiac developmental pathways, cytoskeletal integrity, and electrophysiological mechanisms, supporting a multifactorial genetic architecture of MVP/MAD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/26362147v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@d674a1org.highwire.dtl.DTLVardef@1832397org.highwire.dtl.DTLVardef@95c398org.highwire.dtl.DTLVardef@5c5a83_HPS_FORMAT_FIGEXP M_FIG C_FIG