Objective: To provide a comprehensive and systematic literature review of variants in the glucocerebrosidase 1 gene (GBA1) linked to Parkinson’s disease (PD).

Background: Approximately 10% of patients with PD carry rare (<5% in any population) coding variants in the GBA1 gene, making it numerically the most important genetic risk factor for PD. Biallelic pathogenic variants in GBA1 (e.g., p.N409S, p.L483P) cause Gaucher disease (GD). More than 300 GBA1 variants have previously been reported in conjunction with GD (Sidransky, 2009), and while it is presumed that all these variants are risk factors for PD in the monoallelic state with reduced penetrance, other variants (p.E365K and p.T408M) increase the risk of PD but do not cause GD. The impact of many GBA1 variants on PD risk is still unknown.

Method: This systematic review followed MDSGene’s standardized data extraction protocol with the exception that patients with only group-level data were also included. Titles, abstracts, and full text of articles published in English were screened using PubMed. Articles with clinically affected mutation carriers were included; demographic, clinical, and genetic data were abstracted.

Results: In total, 3,803 publications were screened, and the data from 877 articles from 1965 to mid-2022 were abstracted. Out of 25,881 included individuals, 16,792 (64.9%) had isolated GD, 8,166 (31.5%) isolated PD, 216 (0.8%) GD and PD, 690 (2.7%) other disorders (atypical parkinsonism, ataxia, dystonia) and 17 (0.1%) GD and another disease.

Among 8,166 patients with PD, we identified 288 unique variants, of which we included 260 in MDSGene, the most common being N409S (2,692 cases, 33%), E365K (1,542 cases, 19%), L483P (1,434 cases, 17.5%) and T408M (855 cases, 10.5%). According to ACMG criteria (VarSome, GBA1-PD browser), 121 variants were classified as pathogenic, 67 as likely pathogenic, 59 as a variant of uncertain significance (VUS), 8 as likely benign, and 5 as benign.

Conclusion: We identified 188 pathogenic or likely pathogenic GBA1 variants linked to PD. These results from a comprehensive review of the published phenotypic and genotypic data on the GBA1 gene improve our understanding of the relationship between GBA1 variants and PD and inform the choice of variants for further research and potential inclusion of respective carriers in clinical trials.

References: Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID: 19846850; PMCID: PMC2856322.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/classification-and-genotype-phenotype-relationships-of-gba1-variants-and-parkinsons-disease-mdsgene-systematic-review/