Objective: To identify and describe the genetic features of UK early onset Parkinson’s disease (EOPD) patients.

Background: EOPD with age of onset (AAO) <36 years is rare, affecting fewer than 1% of all PD patients but is a cohort enriched for genetic contribution. Those without molecular diagnosis may harbour yet unidentified variants and/or age of onset may be accelerated due to the cumulative effects of polygenic risk variants and environmental factors.

Method: We recruited 213 Parkinson’s disease patients with AAO <36 between 2005-2026 across three multi-centre UK cohorts: Tracking Parkinson’s disease (PROBAND), Parkinson’s Families Project and CALYPSO. Genetic analysis was carried out using array genotyping, diagnostic-targeted gene analysis or research-based genome sequencing. Copy number variants were identified using CNV-finder on array genotype data or multiplex ligation-dependent probe amplification assay. Ancestries were defined using Genotools and/or self-declared ancestry.

Results: Mean (SD) AAO was 29.5 (6.3) years and mean (SD) disease duration at recruitment was 17 (13.3) years. The majority (87.7%) of participants were of European ancestry, with 4.3% of South Asian and 1.3% of Ashkenazi Jewish ancestry. 29.1% had a family history of Parkinson’s disease, with 8.9% reporting three or more affected family members. 1.4% reported known consanguinity with parents as first cousins. Currently, 14.6% (n=31) have an identified genetic diagnosis: 13.1% (n=28) have biallelic variants in autosomal recessive genes including PRKN (10.8%) with one sibling pair carrying the same variants. Four individuals carried pathogenic variants in DJ1, PINK1, PNPLA6 and SPG7, respectively. Three individuals had autosomal dominant disease with pathogenic LRRK2 variants. 9.4% (n=20) carried single heterozygous variants in autosomal recessive disease genes: 6.1% PRKN (n=13); 1.4% PINK1 (n=3), ATP7B (n=2), SPG11 (n=1), NPC1 (n=1). Most (85.4%) participants do not have identified known pathogenic/likely pathogenic variants in disease causing genes, and further analysis is underway to identify new causal genes and the effect of polygenic risk.

Conclusion: We have identified a large number of EOPD patients. Around 15% have a known genetic aetiology – we are carrying out further analysis to identify new pathogenic genes in the Global Parkinson’s Genetics Program.

References: 1. Towns, C., Fang, ZH., Tan, M.M.X. et al. Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease. npj Parkinsons Dis. 10, 188 (2024). https://doi.org/10.1038/s41531-024-00778-z
2. Vitale D, Koretsky MJ, Kuznetsov N, et al. GenoTools: an open-source Python package for efficient genotype data quality control and analysis. G3 (Bethesda). 2025;15(1):jkae268. doi:10.1093/g3journal/jkae268
3. Kuznetsov N, Daida K, Makarious MB, et al. CNV-Finder: Streamlining Copy Number Variation Discovery. Preprint. bioRxiv. 2025;2024.11.22.624040. Published 2025 Jul 26. doi:10.1101/2024.11.22.624040

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterisation-of-early-onset-parkinsons-disease-in-uk-cohorts/