Objective: To identify and characterize PD patients with RAB32 variant p.Ser71Arg in the ROstock PArkinson’s Disease Study (ROPAD; ClinicalTrials.gov NCT03866603).

Background: A recent preprint provided strong evidence for a single haplotype containing RAB32 variant c.213C>G (p.Ser71Arg) to define a novel form of monogenic Parkinson’s Disease (PD). The authors’ initial suggestive finding was the observation of three variant-positive patients amongst N=130 probands from multi-incident PD pedigrees. Subsequent consultation of several databases identified N=13 additional cases. While the study extensively describes the available data at the patient level, generalizations were hampered by the non-uniformity of information across the diverse patient resources.

Method: We queried our data from phase I of ROPAD, an observational clinical study having enrolled PD patients of mainly European ancestry and employing a standardized case report form (CRF). We first searched for the variant/haplotype of interest in genomes as being available for N=3,354 cases, in whom known monogenic causes for PD had been excluded. We then compared CRF-derived information from variant-positives and variant-negatives.

Results: N=9 of the N=3,354 cases (0.27%) were heterozygous for RAB32 c.213C>G. This is a >100 fold enrichment over the 0.002% in non-Finnish European gnomAD subjects, representing an appropriate control population. Genome sequencing data were in line with all our patients sharing the RAB32 p.Ser71Arg-associated haplotype suggested before. The proportion of females was significantly higher in variant-positives (0.78) than in variant-negatives (0.38) (p=0.03; two-sided Fisher’s exact Test). Though formally non-significant, a higher proportion of variant-positives had a positive family history (0.78 vs 0.47; p=0.09) and received non-L-Dopa PD medication (1.00 vs. 0.74; p=0.12). Variant-positives also had a lower UPDRSIII score (mean 8.4. vs 12.4; p=0.07, two-sided Student’s T-Test), while age at onset was highly similar between variant-positives and variant-negatives (52+/-8 years, vs. 55+/-11 years; p=0.40).

Conclusion: Our observations confirm the hypothesized disease-association of RAB32 c.213C>G, support the existence of a single haplotype with that variant, and suggest that pertinent PD patients may form a unique cohort that is characterized by a specific combination of PD-related features.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rab32-variant-p-ser71arg-in-the-rostock-parkinsons-disease-study-ropad/