Objective: To identify novel monogenic causes of Parkinson’s disease (PD).

Background: The Global Parkinson’s Genetics Program (GP2, http://gp2.org/) is an international collaborative effort that aims to improve our understanding of the role genetics plays in PD and, further, to make this knowledge globally available and actionable [1]. The “Monogenic Hub”, representing one of the two major arms of GP2, aims to perform short or long-read whole-genome sequencing (WGS) for a total of up to 10,000 PD patients starting with a 500-genomes pilot project.

Method: [figure1] We reached out to PD clinicians and researchers from around the globe and collected PD patients from multiplex families, or as singleton cases, in whom a monogenic cause is suspected based on early age at onset (AAO). Clinical and pre-existing genetic data on patients were obtained through online questionnaires and are further collected through the Monogenic Portal, an easy-to-use online application. All submitted cases were evaluated and prioritized for pilot WGS based on the following criteria: number of affected family members and sample availability, pedigree structure, history of consanguinity, AAO, and availability of genetic prescreening. Additionally, particular emphasis was placed on cases from currently underrepresented populations.

Results: Sixteen research teams from 10 different countries submitted 757 PD index patients to the Monogenic Hub. We selected a total of 512 cases for our 500-genomes pilot; ~75% of them were familial cases (with up to nine affected members), and the remaining were singletons with AAO ≤ 40 years, 12 of whom were included as parent-offspring trios. The vast majority (~93%) had some negative genetic pre-screening and about 20% are from underrepresented populations.

Conclusion: Within the Monogenic Hub of GP2, we established a screening process and an online platform for case/family submission (https://monogenic.gp2.org) allowing us to perform WGS for the first 500 PD patients from 279 families with a yet unknown but suspected genetic cause of their PD. This study is anticipated to contribute to the identification of novel monogenic causes of PD.
Following the pilot project, our aim is to be as inclusive as possible and to advertise the project and the Monogenic Portal for (self-)referral of interested sites across the globe [figure2].

References: [1] The Global Parkinson’s Genetics Program. GP2: The Global Parkinson’s Genetics Program. Mov Disord. First published: 29 January 2021. https://doi.org/10.1002/mds.28494.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/monogenic-hub-of-the-global-parkinsons-genetics-program-gp2-the-500-genomes-pilot-project/