Category: Parkinson's Disease: Genetics
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.
References: [1] 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. [2] Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, Tesei S, Zecchinelli AL, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Soldà G, Seresini A, Seia M, Pezzoli G, Goldwurm S. Survival and dementia in GBA-associated Parkinson’s disease: The mutation matters. Ann Neurol. 2016 Nov;80(5):662-673. doi: 10.1002/ana.24777. [3] Blauwendraat C, Reed X, Krohn L, Heilbron K, Bandres-Ciga S, Tan M, Gibbs JR, Hernandez DG, Kumaran R, Langston R, Bonet-Ponce L, Alcalay RN, Hassin-Baer S, Greenbaum L, Iwaki H, Leonard HL, Grenn FP, Ruskey JA, Sabir M, Ahmed S, Makarious MB, Pihlstrøm L, Toft M, van Hilten JJ, Marinus J, Schulte C, Brockmann K, Sharma M, Siitonen A, Majamaa K, Eerola-Rautio J, Tienari PJ; 23andMe Research Team, Pantelyat A, Hillis AE, Dawson TM, Rosenthal LS, Albert MS, Resnick SM, Ferrucci L, Morris CM, Pletnikova O, Troncoso J, Grosset D, Lesage S, Corvol JC, Brice A, Noyce AJ, Masliah E, Wood N, Hardy J, Shulman LM, Jankovic J, Shulman JM, Heutink P, Gasser T, Cannon P, Scholz SW, Morris H, Cookson MR, Nalls MA, Gan-Or Z, Singleton AB. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain. 2020 Jan 1;143(1):234-248. doi: 10.1093/brain/awz350. [4] Lim SY, Tan AH, Ahmad-Annuar A, Klein C, Tan LCS, Rosales RL, Bhidayasiri R, Wu YR, Shang HF, Evans AH, Pal PK, Hattori N, Tan CT, Jeon B, Tan EK, Lang AE. Parkinson’s disease in the Western Pacific Region. Lancet Neurol. 2019 Sep;18(9):865-879. doi: 10.1016/S1474-4422(19)30195-4. [5] Tan AH, Lohmann K, Tay YW, Lim JL, Ahmad-Annuar A, Ramli N, Chin YT, Mawardi AS, Azmi K, Aziz ZA, Puvanarajah SD, Bauer P, Klein C, Rolfs A, Lim SY. PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases. Parkinsonism Relat Disord. 2020 Aug 19;79:34-39. doi: 10.1016/j.parkreldis.2020.08.015. [6] Klein C, Hattori N, Marras C. MDSGene: Closing Data Gaps in Genotype-Phenotype Correlations of Monogenic Parkinson’s Disease. J Parkinsons Dis. 2018;8(s1):S25-S30. doi: 10.3233/JPD-181505.
To cite this abstract in AMA style:
JL. Lim, K. Lohmann, AH. Tan, YW. Tay, KA. Ibrahim, Z. Abdul Aziz, AS. Mawardi, S. Datuk Puvanarajah, I. Looi, YK. Chia, TT. Lim, P. Bauer, A. Rolfs, C. Klein, A. Ahmad-Annuar, S-Y. Lim. GBA variants in a multi-ethnic Parkinson’s disease (PD) cohort in Malaysia [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/gba-variants-in-a-multi-ethnic-parkinsons-disease-pd-cohort-in-malaysia/. Accessed December 1, 2024.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-variants-in-a-multi-ethnic-parkinsons-disease-pd-cohort-in-malaysia/