Genetics of Parkinson’s disease in a cohort of Sudanese Population

Abstract

Parkinson's disease (PD) is a progressive neurological disorder that affects various regions of the brain, particularly the substantia nigra (SNr). The prevalence of PD is estimated 1 in 1000 in undisclosed populations, and PD impacts around 1% of individuals over 60 years old. The annual occurrence of PD per 100,000 people ranges from 10 to 20. Currently, the diagnosis of PD relies mainly on clinical criteria as there are no cheap and easy available biological markers. It can be challenging to diagnose PD accurately, as its characteristic symptoms may also be present in other disorders, making it necessary to conduct further investigations to rule out alternative causes of Parkinsonism. Studies have suggested a potential genetic connection between disease-causing mutations and risk-associated variants in PD. However, there is limited research in Sudan regarding the role of genetics (and epigenetics) in adult PD. In the studies presented herin, DNA methylation, mutation screening and whole exome sequencing was performed to elucidate the implications of known and candidate genes. DNA from 172 Sudanese individuals, comprising 90 cases and 82 controls, who provided saliva for DNA extraction was analyzed. The average age of onset was 40.6 ± 22.4 years, and 64 patients had a family history of PD. Bisulfite sequencing of a-synuclein (SNCA) intron1 was performed and DNA from 66 individuals, representing 30 families, was analyzed using the Twist custom panel, which allows for screening of 34 genes, 27 risk factors, and 8 candidate qualities associated with Parkinsonism. <br> To capture the relevant genetic information, the custom Design KAPPA Library Preparation Kit from Roche was utilized, targeting exons, intron-exon boundaries, 5'- and 3'-UTR sequences, and 10-bp flanking sequences of the selected genes based on the RefSeq database (hg38 assembly). Whole exome sequencing was conducted using the Illumina NovaSeq 6000 sequencer, achieving a median coverage of 100x and generatig paired-end reads of 100 base pairs. The targeted NGS panel successfully identified both known and novel mutations in six out of thirtysix families, resulting in a diagnostic rate of 20%, consistent with previously reported rates. Moreover, the average number of diagnosed patients per family using the panel was found to be 3.7 ± 2.3 for families with identified mutations and 1.8 ± 1.5 for unresolved families. This suggests that the targeted gene panel could be a valuable tool for investigating families with two or more affected individuals. Additionally, novel variants in candidate genes were discovered in one or more families, which could potentially contribute to disease development or susceptibility to Parkinson's disease.