Objective: To investigate the frequency of Glucocerebrosidase (GBA) gene variants in a multi-ethnic Parkinson’s disease (PD) cohort in Malaysia.

Background: GBA variants have been associated with an up to 10-fold increased risk of developing PD, and a more rapid progression of disease, particularly with “severe” mutations such as p.L483P [1-3]. While more than 300 mutations in GBA have been reported, studies in Asian populations remain limited [4].

Method: Genetic testing was performed in 496 PD patients (57% male) recruited from seven tertiary medical centres in Malaysia. Patients were of Chinese (n=223), Malay (n=185), Indian (n=63), and other/mixed ethnicities (n=25). All GBA, SNCA, LRRK2, PRKN, PINK1 and DJ-1 exons were screened using an NGS-based PD gene panel (Centogene AG, Rostock, Germany) [5]. GBA variants were further verified using in-house PCR primers and Sanger sequencing.

Results: Fourteen coding GBA variants (8 previously reported as pathogenic/likely pathogenic and 6 with unknown significance) were identified in 25 out of 496 patients (5.0%). The most common variant found was p.L483P (n=11/496, 2.2%); the majority of the variant carriers were of Chinese ancestry (n=8/223, 3.5% of Chinese cases). Other pathogenic/likely pathogenic variants included p.R159Q (0.4%), p.G241R (0.4%), p.S146L (0.2%), p.N227S (0.2%), p.S310G (0.2%), p.H350R (0.2%), and p.D448H (0.2%). The p.N409S, p.E365K and p.T408M variants (most commonly found among European/Ashkenazi Jewish patients) were not detected. Of the 20 PD patients with pathogenic/likely pathogenic GBA variants, 12 (60.0%) had early-onset PD (<50 years) and five (25.0%) had a family history of PD. Mean age at PD diagnosis was significantly younger in these patients compared to GBA pathogenic variant-negative patients (46.2±11.6 vs. 56.9±13.1years, p<0.001). The frequency of known pathogenic/likely pathogenic GBA variants was 4.0% (n=9) in Chinese patients, 4.3% (n=8) in Malays, and 4.8% (n=3) in Indians.

Conclusion: GBA variants were a relatively frequent finding in our cohort of multi-ethnic Malaysian patients, with p.L483P being the most common variant. A number of variants of unknown significance were detected. Further genotype-phenotype [6] and functional studies will improve our understanding of the role of GBA variants in PD pathogenesis in the Malaysian population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-variants-in-a-multi-ethnic-parkinsons-disease-pd-cohort-in-malaysia/