Arrhythmogenic mitral valve prolapse and underlying cardiomyopathic substrates: a genetic case-control Study using UK Biobank and NIH all of Us

Background Arrhythmogenic mitral valve prolapse (aMVP) has been associated with malignant ventricular arrhythmias and sudden cardiac death(1). Whether aMVP represents a distinct genetic entity or reflects phenotypic overlap with underlying cardiomyopathic or inherited arrhythmia substrates remains unclear. Purpose To evaluate the burden of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy and channelopathy genes among patients labelled as aMVP compared with non-arrhythmogenic MVP, and to explore whether observed enrichment may reflect diagnostic boundary effects. Methods We conducted a retrospective genetic case–control study including consecutive patients with aMVP evaluated at a tertiary Inherited Cardiovascular Disease Center (2020–2025). Comparator cohorts included individuals with MVP without documented ventricular arrhythmias from the UK Biobank and NIH All of Us (Figure 1). All aMVP patients underwent comprehensive genetic testing and deep phenotyping. The primary endpoint was prevalence of Mendelian P/LP variants. Secondary outcomes included clinical, electrocardiographic, and cardiac magnetic resonance features associated with genotype-positive status. Results Among 3,432 individuals with MVP (62 aMVP, mean age 61.8 years with 50% female; 3,370 non-arrhythmogenic MVP), P/LP variants were more frequent in aMVP (42.9%) than in controls (2.3%; p<0.001). In aMVP, genotype-positive individuals showed higher prevalence of cardiomyopathy phenotype diagnosis (76.2% vs 29.6%; p<0.001), inferior T-wave inversion (29.4% vs 3.8%; p=0.018), and basal inferoseptal late gadolinium enhancement (33.3% vs 4%; p=0.010) (Figure 2). On multivariable analysis, phenotypic cardiomyopathy diagnosis remained independently associated with genotype-positive status. Conclusion Patients labelled as aMVP demonstrate significant enrichment of pathogenic variants linked to inherited cardiomyopathies and arrhythmia syndromes. The strong association between genotype positivity and phenotypic cardiomyopathy features suggests that part of the genetic enrichment attributed to aMVP may reflect phenotypic overlap and diagnostic boundary effects with underlying cardiomyopathic substrates rather than MVP-specific genetic causation. These findings support systematic deep phenotyping and genetic evaluation in MVP patients presenting with ventricular arrhythmias.