This study finds significant enrichment of likely pathogenic VPS13C variants in idiopathic REM sleep behavior disorder (iRBD), especially the iRBD-first α-synucleinopathy subtype, and links carriers to worse RBD symptoms, autonomic and REM EEG abnormalities, and faster conversion to overt…

By nominating VPS13C variants as a prodromal genetic marker that predicts phenotype severity and accelerated conversion, the work enables patient stratification for early intervention trials and supports functional follow-up of VPS13C-linked pathways (e.g., lysosomal/mitochondrial biology) for…

While VPS13C is a recessively inherited Parkinson's disease (PD) gene, its potential dominant effects in idiopathic Rapid-eye movement (REM) sleep behavior disorder (iRBD) remain unexplored. The relation between its monogenic form and the onset of PD suggested that subtype specificity may need to be considered. We examined the presence of likely pathogenic VPS13C variants in 150 iRBD and 180 α-synucleinopathy patients (iRBD-first and movement disorder-first). VPS13C variants were significantly enriched in iRBD patients, and ten iRBD risk variants have been identified. iRBD risk VPS13C variant carriers demonstrated more severe RBD symptoms and greater autonomic dysfunction, correlating with REM sleep EEG and autonomic network activity abnormalities. Notably, enrichment was specific to the iRBD-first α-synucleinopathy subtype, and iRBD risk VPS13C variant carriers showed accelerated progression to overt α-synucleinopathy. These results suggest that VPS13C not only contributes to iRBD susceptibility but also serves as a marker for the iRBD-first α-synucleinopathy and faster disease conversion.