Genetic Analysis of in an Early-Onset Parkinson's Disease Cohort.

Pathogenic variants in the gene encoding RAB39B, resulting in the loss of protein function, lead to the development of X-linked early-onset parkinsonism. The gene is located within a chromosomal region that is susceptible to genomic rearrangement, and while an increased dosage of was previously associated with cognitive impairment, the potential role of dosage alterations in Parkinson's disease (PD) remains to be determined. This study aimed to investigate the contribution of the genetic variation in RAB39B to the development of early-onset PD. We performed gene dosage studies and sequence analysis in a cohort of 176 individuals with early-onset PD (age of onset ≤ 50 years) of unknown genetic etiology. An assessment of the copy number variation over both coding exons and the 3' untranslated region (UTR) of did not identify any alterations in gene dosage. An analysis of the UTRs identified two male individuals carrying single, likely benign, nucleotide variants in the 3'UTR (chrX:154489749-A-G and chrX:154489197-T-G). Furthermore, one novel variant of uncertain significance was identified in the 5'UTR, 229 bp upstream of the start codon (chrX:154493802-C-T). analyses predicted that this variant disrupts a highly conserved transcription factor binding site and could impact expression. The results of this study do not support a significant role for genetic variation in as contributing to early-onset PD but do highlight that additional molecular studies are required to determine the mechanisms regulating expression and their association with the disease. Genetic investigations in larger parkinsonism/PD cohorts and longitudinal studies of individuals with cognitive impairment due to an altered dosage of will be required to fully delineate the contribution of RAB39B to parkinsonism.