Objective: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort.

Background: About 5-10% of Parkinson’s disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and global studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic pathways.

Method: 161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification.

Results: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic GBA variants were identified in thirteen patients (8.1%). PRKN and PINK1 were also commonly implicated (11/161=6.8% and 6/161=3.7%, respectively). The yield was even higher in those with familial history (48.5%) or age of diagnosis £40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes.

Conclusion: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-study-of-early-onset-parkinsons-disease-in-the-malaysian-population/