Objective: To identify individuals with rare pathogenic and potentially pathogenic variants of unknown significance (VUS) in PPP2R5D within large Parkinson’s disease (PD) cohorts, to characterize the clinical features of PPP2R5D‑related parkinsonism and to expand the catalog of PD‑related PPP2R5D pathogenic variants.

Background: PPP2R5D encodes the regulatory subunit of a protein phosphatase, involved in modulating dopaminergic neurotransmission in neurons. De novo variants in PPP2R5D are associated with Jordan Syndrome, characterized by neurodevelopmental delay, autism spectrum disorder, dysmorphic features, speech impairment, and seizures. To date, only a small number of PPP2R5D pathogenic variant carriers with early-onset parkinsonism with good response to levodopa have been reported. Most pathogenic variants are missense changes affecting three distinct conserved regions within the protein (amino acids 193-211, 246-256, 415-427).

Method: We extracted exonic and splicing variants in 21,858 PD cases and 9,172 controls from the Global Parkinson’s Genetic Program (GP2) and 14,648 PD cases from the PD GENEration clinical exome sequencing (CES) cohort. 2,463 additional PD cases were analyzed from the Paris Brain Institute. We categorized pathogenic variants following the American College of Medical Genetics and Genomics (ACMG) criteria. In addition, we selected high priority VUS that were absent in GP2 controls and located in one of the three highly conserved protein regions where known pathogenic variants cluster.

Results: Across the three cohorts (n = 38,920 PD cases), we identified four heterozygous pathogenic variants in 17 unrelated patients (0.0004%) and 0 in controls (Table 1). The most frequent variant was p.E200K (n = 13). The median age at onset (AAO) across all variant carriers was 38 (Range 24-62) years.

Moreover, we identified six high-priority VUS meeting our inclusion criteria in six additional patients (Table 2). The median AAO of VUS PD carriers was 35 (Range 31-50) years.

Conclusion: Here, we report 17 patients diagnosed with PD carrying pathogenic variants in PPP2R5D and 6 additional carrying high-priority VUS . Our work highlights PPP2R5D as a potential cause of PD, supporting its inclusion in the genetic workup of PD. Collection of additional clinical data as well as burden test analysis are ongoing.

Table 1

Table 2

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ppp2r5d-variants-in-patients-diagnosed-with-parkinsons-disease-a-large-scale-multi-cohort-analysis/