Objective: Investigate EPG5 role in PD aetiology.

Background: Disruption of the lysosome-autophagy pathway is a recurrent feature in Parkinson’s disease (PD). EPG5 bi-allelic loss-of-function variants have been shown to cause Vici Syndrome, a congenital disorder of autophagy. Recent evidence suggests variants in this gene could be causative of atypical parkinsonism in adults.

Method: This study was a collaboration between the Global Parkinson Disease Program (GP2) and the Paris Brain Institute. Our investigations included identification of carriers of EPG5 bi-allelic variants in GP2, as well as rare variant burden tests and linear regression analyses in GP2 and the UK Biobank (UKB) data sets to explore the cumulative role of variants. Simultaneously, individuals with pathogenic homozygous and compound heterozygous (CH) variants from the French Parkinson Disease Genetics Study Group (PDG) whole exome sequencing (WES) and whole genome long-read sequencing (LRS) PD cohorts were selected. Functional studies on patient-derived fibroblasts as well as C. elegans and Drosophila animal models were also performed.

Results: A total of 18,219 PD participants were included in the variant extraction process from GP2 whole genome (WGS) multi-ancestry cohort. We identified 21 potential bi-allelic variants,19 missense and two stop-gain, in a total of 12 individuals. Of the latter, five met the criteria of early onset PD (≤ 50yrs) without genetic evidence of autosomal dominant family history. Variant phase analysis confirmed compound heterozygosity in two patients. From the PDG (total 2,108 WES, 125 LRS) two pedigrees were identified. In the first one, five affected siblings carried a homozygous missense variant identified by WES. In the second, two affected siblings carried a CH deletion and missense variant.

In all cases identified, the phenotype was an atypical, rapidly progressive parkinsonism with dystonic features and early cognitive impairment. Our burden analysis on UKBB and GP2 did not reveal enrichment of rare damaging variants. Functional works revealed decreased EPG5 protein level and impaired lysosomal function in patient-derived fibroblasts, and impaired locomotor phenotype in C.elegans and Drosophila studies.

Conclusion: Our study confirms that EPG5 gene bi-allelic variants cause early-onset atypical parkinsonism. Further clinical classifications of the identified individuals are necessary to better characterise the role of EPG5 in typical PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-role-of-biallelic-epg5-variants-in-parkinsons-disease/