Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: Mutational spectrum and clinical features

Lim, Jia Lun and Lohmann, Katja and Tan, Ai Huey and Tay, Yi Wen and Ibrahim, Khairul Azmi and Aziz, Zariah Abdul and Mawardi, Ahmad Shahir and Puvanarajah, Santhi Datuk and Lim, Thien Thien and Looi, Irene and Ooi, Joshua Chin Ern and Chia, Yuen Kang and Muthusamy, Kalai Arasu and Bauer, Peter and Rolfs, Arndt and Klein, Christine and Ahmad-Annuar, Azlina and Lim, Shen-Yang (2022) Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: Mutational spectrum and clinical features. Journal of Neural Transmission, 129 (1). pp. 37-48. ISSN 0300-9564, DOI

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GBA variants are associated with increased risk and earlier onset of Parkinson's disease (PD), and more rapid disease progression especially with ``severe'' variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50 years) vs. late-onset patients across all three ethnicities (9.1-13.2% vs. 1.0-3.2%). The most common variant was p.L483P (including RecNciI, n = 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of GBA-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in GBA-variant carriers. This represents the largest study on GBA variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting GBA pathways.

Item Type: Article
Funders: Ministry of Higher Education Malaysia Fundamental Research Grant Scheme[FRGS/1/2018/SKK08/UM/02/3], University of Malaya Parkinson's Disease and Movement Disorders Research Program[PV035-2017]
Uncontrolled Keywords: Parkinson's disease;GBA;Genetics;Early-onset PD;Camptocormia
Subjects: R Medicine
R Medicine > R Medicine (General)
R Medicine > RA Public aspects of medicine
R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 25 Jul 2022 04:22
Last Modified: 25 Jul 2022 04:22

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