Journal
FRONTIERS IN NEUROSCIENCE
Volume 16, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2022.817713
Keywords
whole-exome sequencing; parkinsonism; neurodegenerative disorders; trio analysis
Categories
Funding
- Ministry of Health of the Czech Republic [15-32715A]
- Palacky University Medical School Internal Grant Agency [IGA LF 2018-009, IGA LF 2020-017, IGA LF 2022014]
- Ministry of Health of the Czech Republic: conceptual development of research organization MH CZ -DRO (FNOL) [00098892]
- European Regional Development Fund [CZ.02.1.01/0.0/0.0/16_019/0000868]
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Parkinsonism is a common neurodegenerative disease, and this study focused on the genetic predisposition and variants in a Moravian pedigree. Whole exome sequencing was performed on five family trios, and the presence of genetic variants related to Parkinsonism was evaluated. Although no founder mutations were found, shared variants were identified among different trios. The study suggests the accumulation of multiple risk genetic factors for Parkinsonism in the isolated Moravian population.
Parkinsonism belongs to the most common neurodegenerative disease. Genetic predisposition could be one of the significant risk factor for disease development. It has been described higher prevalence of parkinsonism in large pedigree from southeastern Moravia region. The study aims were to select accessible subfamily trios from the pedigree suitable for segregation genetic analyses to perform whole exome sequencing (WES) in trio individuals and further to evaluate genetic variants in the each trio. We used IonTorrent platform for WES for five subfamily trios (1-5). Each trio included two affected and one healthy person (as control). Found variants were filtered with respect to MAF < 1% (minor allele frequency), variants effect (based on prediction tools) and disease filter (Parkinsonism responsible genes). Finally, the variants from each trio were assessed with respect to the presence in the patients. There were found no one founder mutation in the subfamilies from the pedigree. Trio 1 shares two variants with trio 2:MC1R:c.322G > A (p.A108T) and MTCL1:c.1445C > T (p.A482V), trio 3 shares two variants with trio 5: DNAJC6:c.1817A > C (p.H606P) and HIVEP3:c.3856C > A (p.R1286W). In trios 4 and 5, there were found two variants in gene CSMD1:c.3335A > G (p.E1112G) and c.4071C > G (p.I1357M) respectively. As the most potentially damaging, we evaluated the non-shared variant SLC18A2:c.583G > A (p.G195S). The variant could affect dopamine transport in dopaminergic neurons. The study of the parkinsonism genetic background in isolated Moravian population suggested that there could be significant accumulation of many risk genetic factors. For verification of the variants influence, it would be appropriate to perform a more extensive population study and suitable functional analysis.
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