Very High Frequency of Early-Onset Parkinson's Disease and PRKN Mutations among Indigenous Patients in Sabah, Malaysia.

BACKGROUND Early-onset Parkinson's disease (EOPD) affects approximately 10% to 20% of PD patients, with PRKN mutations being the commonest cause. Genetic studies on EOPD in Southeast Asians, especially indigenous populations, are limited. OBJECTIVES To investigate the frequency and clinical phenotypes of EOPD and PRKN mutations in indigenous populations from Sabah state, Malaysia, and to further characterize the high-frequency PRKN exon 3 deletion in this cohort via breakpoint mapping. METHODS We recruited 284 indigenous Sabahans (184 PD patients, comprising 157 probands and 100 controls). Patients were clinically phenotyped, and PRKN mutational screening and breakpoint mapping performed using multiplex ligation-dependent probe amplification, polymerase chain reaction, and Sanger sequencing. RESULTS Notably, 43.9% (n = 69/157) of probands had EOPD. Among them, 56.5% (n = 39/69) carried biallelic PRKN mutations, with homozygous exon 3 deletion accounting for two-thirds of the mutations. Remarkably, all PRKN-PD patients carried at least one exon 3 deletion. Patients of the Dusun tribe had the highest frequency of biallelic PRKN mutations (61.8%). Two unique PRKN exon 3 deletion breakpoints were identified in all carriers, suggesting a possible founder effect. Among PRKN-PD patients, those with homozygous exon 3 deletions had a non-significant earlier age of onset (35.8 ± 10.2 vs. 40.1 ± 9.9) and worse disability after controlling for age and disease duration. CONCLUSION We found a strikingly high prevalence of EOPD and PRKN mutations in indigenous Sabahans, contributing novel data to the very scarce PD genetics literature on global indigenous populations, and highlighting the discovery of populations at high risk of EOPD possibly due to a combination of founder effect and consanguinity. © 2025 International Parkinson and Movement Disorder Society.