Biallelic Variants in EPG5 Gene Are Associated with Parkinson's Disease

Objective Despite substantial advancements in uncovering the genetic basis of Parkinson's disease (PD), a significant portion of cases characterized by familial PD remain genetically elusive. Here, we reported that biallelic variants in EPG5 , a key autophagy gene responsible for Vici syndrome, are associated with PD. Methods Whole‐exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early‐onset PD (sEOPD, age at onset ≤ 50 years) and 1,652 healthy controls. Whole‐genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late‐onset PD (sLOPD, age at onset >50 years) and 2,478 healthy controls. Results We identified 7 participants harboring compound heterozygous variants within the EPG5 gene across 1 family with ARPD (ARPD‐F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in EPG5 were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the EPG5 gene led to decreased expression of EPG5 protein, and impaired autophagy‐lysosome function in cells derived from EPG5 ‐PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of α‐synuclein in skin tissue from EPG5 ‐PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain. Interpretation Our results unveil a novel association between biallelic variants in EPG5 gene and PD, providing compelling initial evidence for the involvement of EPG5 and autophagy dysregulation in the development of PD. ANN NEUROL 2025