Genetic study of early-onset Parkinson's disease in the Malaysian population

Background: About 5-10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes impli-cated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across pop-ulations and globally diverse 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 variants.Objectives: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort.Methods: 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 (MLPA).Results: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate 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.Conclusions: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, ex-pands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.