Objective: The aim of the work is to identify new genes involved in autosomal recessive (AR) early-onset (EO, >40 years) Parkinson disease (PD), using consanguineous PD families and applying genotyping on DNA microarrays and NGS technologies.

Background: Parkinson disease (PD) affects 1% of the population above 65 years. It is characterized by the triad of symptoms: tremor, rigidity, and bradykinesia. To date, more than 10 validated genes have been identified, associated with either autosomal dominant (AD) or recessive (AR) forms of PD. However, the identified genes associated with EO AR PD only explain 45%, other genes remain to be discovered.

Method: We selected 99 families that fulfilled the following criteria: •        Age at onset ≤50 years •        Confirmed consanguinity •        Excluded for mutations in known AR PD associated-genes We performed exome sequencing and looked for rare homozygous variants, predicted to be pathogenic and rare in the public databases (MAF<1%).

Results: Using a series of 99 families with confirmed consanguinity, we looked for homozygous loss of function or missense mutations predicted deleterious in region of loss of homozygosity. Then we first focused on variant shared by at least two families. We identified mutations in PSMF1 an interactor of FBXO7. In one families, it remains only this variant moreover both mutations code for amino acid highly conserved upon evolution. Most of the candidate’s genes are private genes highlighting genetic heterogeneity of PD. Therefore, in a second time we hypothesized that some candidate’s genes can be involved in a common pathway. Using ClusterProfiler we performed GO term enrichment analyses, then we were able to grouped together some genes and were able to see an statistical enrichment in autophagy pathway.

Conclusion: We identified a strong candidate gene for AR-PD: PSMF1. Further functional data are needed to strengthen the role of this gene in PD, possibly affecting the proteasome activity and α-synucleine aggregation. We will also continue to investigate pathway analyses in order to identify candidates for PD in our families.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-potential-new-genes-involved-in-autosomal-recessive-forms-of-parkinsons-disease/