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Here, we reported that biallelic variants in <jats:italic>EPG5<\/jats:italic>, a key autophagy gene responsible for Vici syndrome, are associated with PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early\u2010onset PD (sEOPD, age at onset \u2264\u200950\u2009years) and 1,652 healthy controls. Whole\u2010genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late\u2010onset PD (sLOPD, age at onset &gt;50\u2009years) and 2,478 healthy controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 7 participants harboring compound heterozygous variants within the <jats:italic>EPG5<\/jats:italic> gene across 1 family with ARPD (ARPD\u2010F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in <jats:italic>EPG5<\/jats:italic> were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the <jats:italic>EPG5<\/jats:italic> gene led to decreased expression of EPG5 protein, and impaired autophagy\u2010lysosome function in cells derived from <jats:italic>EPG5<\/jats:italic>\u2010PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of \u03b1\u2010synuclein in skin tissue from <jats:italic>EPG5<\/jats:italic>\u2010PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our results unveil a novel association between biallelic variants in <jats:italic>EPG5<\/jats:italic> gene and PD, providing compelling initial evidence for the involvement of <jats:italic>EPG5<\/jats:italic> and autophagy dysregulation in the development of PD. ANN NEUROL 2025;98:369\u2013385<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.27242","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T08:42:04Z","timestamp":1744015324000},"page":"369-385","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Biallelic Variants in <scp><i>EPG5<\/i><\/scp> Gene Are Associated with Parkinson's Disease"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2031-8345","authenticated-orcid":false,"given":"Qi\u2010Ying","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Neurology, Department of Geriatrics Xiangya Hospital, Central South University  Changsha China"},{"name":"Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital Central South University  Changsha China"},{"name":"National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University  Changsha 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