Objective: The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD).

Background: Rare variants in several genes have been reported to cause monogenic PD. In unselected PD populations, known rare causal variants account for around 5-10% of cases. However, a family history of PD and an early age at onset are associated with an increased likelihood of carrying a pathogenic mutation. We have set up the Parkinson’s Families Project to enable the discovery of novel mutations and/or genes causing monogenic PD.

Method: We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤ 45 years and/or a family history of PD. Where possible, we also recruited affected and unaffected family members for segregation studies. We analysed DNA samples with a combination of single nucleotide polymorphism array genotyping, multiplex ligation-dependent probe amplification, and whole genome sequencing in the Global Parkinson’s Genetics Program. We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA).

Results: We performed genetic analysis of the first 714 recruited families, of which 196 had sporadic early-onset PD, 112 had familial early-onset PD and 406 had late-onset familial PD. The mean age of motor symptom onset was 52 ± 15.1 years. The average family size in familial cases was 2.1 ± 1 affected individuals. 53 (7.4%) of these families carried pathogenic variants in known PD-associated genes. We identified pathogenic mutations in LRRK2 in 4.1% of families, and bi-allelic pathogenic mutations in PRKN in 2.4% of families. We also identified pathogenic mutations in two families with SNCA duplications, and single families with pathogenic mutations in VCP, PINK1, PNPLA6, PLA2G6 and SPG7.

Conclusion: For the vast majority of early-onset and familial PD cases, a known genetic cause has not yet been identified, suggesting either that there are additional monogenic forms to discover and/or that some PD families have more complex inheritance. Further analysis of whole genome sequencing is currently under way to identify novel variants and/or genes causing monogenic PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-families-project-a-uk-wide-study-of-early-onset-and-familial-parkinsons-disease/