In 203 consecutive mitral valve prolapse (MVP) patients without other arrhythmic substrates, whole exome sequencing identified pathogenic or likely pathogenic (P/LP) cardiomyopathy and channelopathy (CC) gene variants in 9% of individuals — spanning 8 distinct variants across 12 genes. These P/LP carriers faced an independent 2.87-fold greater hazard of severe arrhythmic outcomes (sudden cardiac death, ventricular fibrillation, or requiring defibrillator implantation), even after controlling for established imaging risk markers like mitral annular disjunction and bileaflet involvement. CC variants overall appeared 4.3 times more frequently in MVP patients than in the general gnomAD population.
MVP affects roughly 2–3% of the general population and is frequently dismissed as benign, yet a clinically important subset experiences life-threatening arrhythmias — a phenomenon poorly predicted by current echocardiographic criteria alone. This study meaningfully advances risk stratification by demonstrating that genetic profiling adds independent predictive value beyond imaging, potentially identifying patients who warrant earlier electrophysiological monitoring or prophylactic intervention. The finding aligns with emerging evidence of a myopathic substrate in arrhythmic MVP, bridging structural and genetic cardiology.
Critical limitations deserve emphasis: the cohort of 203 patients remains modest, the composite arrhythmic endpoint blends outcomes of varying severity, and causality cannot be established from this design. As a preprint posted to medRxiv and not yet peer-reviewed, these findings require independent replication and formal peer scrutiny before influencing clinical genetic testing protocols. If validated, routine CC gene panel screening could meaningfully reshape MVP management guidelines.