Parkinson's families project: a UK-wide study of early onset and familial Parkinson's disease.
Level 4 - case-series / case-control
Case-series / observational genetic screening study of a targeted clinical cohort
PubMed 39420034 · doi:10.1038/s41531-024-00778-z
What was done
The Parkinson's Families Project recruited individuals across the UK with clinically diagnosed Parkinson's disease (PD) who had motor symptom onset at or before age 45, a family history of PD up to third-degree relatives, or both, alongside available relatives. Investigators performed baseline genetic testing in 718 families (205 sporadic early-onset, 113 familial early-onset, and 400 familial late-onset) using SNP array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). They evaluated pathogenic mutations alongside age at motor symptom onset, family history, MDS-UPDRS, and MoCA scores.
What was found
Pathogenic variants in known monogenic PD-related genes were identified in 69 of 718 families (9.6%). Diagnostic yield rose to 28.1% in cases with motor onset at or before 35 years. Pathogenic variants occurred most often in LRRK2 (4.2% of families) and as biallelic PRKN variants (3.6% of families). Other findings included SNCA duplications (2 families), ATXN2 repeat expansions (3 families), and single families with variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 families (10.2%) carried at least one pathogenic or risk GBA1 variant.
Why it matters
The findings establish diagnostic yields for early-onset and familial PD in the UK, highlighting high yield in onset before age 35 while demonstrating that over 90% of familial and early-onset cases remain genetically unexplained by known monogenic variants.
Limits
The study is restricted to a UK population, limiting generalizability to other ancestries. Quantitative outcomes for the planned associations between genotypes and clinical measures (MDS-UPDRS and MoCA scores) are not reported in the abstract.
Cited by
- supports Strong genetic contributions to Parkinson's disease are predominantly found in young-onset cases occurring under the age of 35.