Objective: To clinically and genetically characterize a global sample of subjects with monogenic Parkinson’s disease (mPD) and unaffected mutation carriers.

Background: Publications on patients with mPD often include limited phenotypic data. Likewise, although there is strong evidence for ethnicity-specific pheno- and genotypes, clinical and genetic information on mPD is currently available for a subset of ethnicities only and with small case numbers for each ethnicity.

Method: We invited researchers in the field of mPD to share a pre-defined set of retrospective clinical and genetic data on any affected and unaffected subjects with mutations in mPD genes for typical dominant or recessive PD (LRRK2, Parkin, SNCA, PINK1, VPS35, and DJ1). After harmonizing and curating including thorough quality checks of the obtained data, we evaluated the pathogenicity of the reported genetic variants according to MDSGene criteria.

Results: In total, we received data on 5015 individuals. N=2578 passed quality checks and carried at least one mutation evaluated as possibly (n=105), probably (n=224) or definitely pathogenic (n=2249). Subjects originate from >50 countries covering all continents and ethnicities are correspondingly diverse. 2093 subjects were reported to have mPD (50% male), 485 were unaffected (48% male). Subjects carried mutations in LRRK2 (1287 mPD/322 unaffected), Parkin (401 biallelic; 177 monoallelic/1 biallelic; 83 monoallelic), SNCA (108/31), PINK1(62 biallelic; 24 monoallelic/1 biallelic; 41 monoallelic), VPS35 (21/3), and DJ1 (9 biallelic; 4 monoallelic/3 monoallelic). The most frequently reported variant was p.G2019S in LRRK2 (1128/263).

Conclusion: We successfully implemented a worldwide collaborative approach to establish the MJFF Global Genetic PD Cohort. >150 researchers from 82 centers on all continents participated in this effort and volunteered to share genetic and clinical data on their cases. The distribution of cases across genes approximately reflects the ratio of published cases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterizing-global-cohorts-with-monogenic-parkinsons-disease/