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Background: Recently, homozygous variants in PTPA were identified as the disease cause for two pedigrees with early‐onset parkinsonism and intellectual disability. Although the initial link between PTPA and parkinsonism has been established, further replication was still necessary. Objectives: To evaluate the genetic role of PTPA in Parkinson's disease (PD). Methods: We analyzed rare variants of PTPA in cohorts of Asian and European ancestries (Ncase = 2743, Ncontrol = 8177) with whole‐exome sequencing, and further explored the functional effect of the target variant. Results: One patient with early‐onset PD from a consanguineous family carried the homozygous variant p.Met329Val, while her parents and elder sister with heterozygous p.Met329Val were healthy. This patient developed minor cognitive decline within 1 year, with a Montreal Cognitive Assessment (MoCA) score dropping from 28 to 25. Functional exploration with overexpression studies suggested that this variant was associated with decreased protein phosphatase 2A (PTPA) protein level by affecting protein stability, but not mRNA expression. Conclusions: These results have broadened the mutation spectrum of PTPA, and paved the way for further research into the role of PTPA in PD. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Homozygous missense variants in PTRHD1 have been identified to cause parkinsonism by segregation analysis in families. Further replication in the Parkinson's disease (PD) population might provide additional insight. Here, we analyzed the rare variants in a Chinese PD cohort (Ncase = 1367, Ncontrol = 3298) with whole exome sequencing. We did not identify the variants described in previous studies, and no patient carried other homozygous or compound heterozygous variants of PTRHD1. Three rare variants were identified, but rare variants of PTRHD1 were not enriched in PD. Genetic screening suggested rare variants of PTRHD1 as disease cause were rare in PD in East Asians. [ABSTRACT FROM AUTHOR]