Comprehensive genetic screening of the south African Parkinson's disease study collection using the NeuroBooster array

Introduction Although there have been significant advances in the genetic etiology of Parkinson's disease (PD), most of this research has been conducted in European populations. This study aimed to characterize the genetic landscape of PD in South Africa, whose populations are renowned for their extensive genetic diversity and admixture. Methods We recruited 689 PD probands across South Africa. These participants were genotyped using the NeuroBooster array in collaboration with the Global Parkinson's Genetics Program (GP2). An in-house computational workflow was used to identify pathogenic missense variants, which were validated using Sanger sequencing. The CNV-Finder pipeline was used to screen for copy number variations (CNVs), which were validated using Multiplex Ligation-dependent Probe Amplification (MLPA). Previously identified pathogenic variants were used as positive controls in our analysis. Results We identified 16 unique missense variants in 47 individuals, 15 of which were independently confirmed by Sanger sequencing. However, these variants are not considered likely to be associated with PD status. We also identified new homozygous PRKN CNVs in three individuals and a whole-gene SNCA duplication in one individual, all of which were validated by MLPA. In addition, one individual had a CNV in the 5′ untranslated region of SNCA , although its pathogenicity remains unclear. When these findings were combined with our previous results, 3.5% of probands (24 individuals) were found to have a genetic basis for their disease. Conclusions We conducted the largest pathogenic variant screening to date in this unique and underrepresented population, and our findings highlight the rare contribution of known pathogenic variants. This study underscores the importance of expanding genetic research in African cohorts to improve global understanding of PD etiology.