Objective: The aim of the study was to investigate a co-occurence of rare variants in set of genes frequently associated with parkinsonism.

Background: The increased prevalence of neurodegenerative parkinsonism was detected in population of a small isolated region of south-eastern Czech Republic

Method: The molecular genetic examination was performed in 32 probands with parkinsonism and 20 asymptomatic controls from region under study. Coding sequences, exon/intron regions and 5´/3´UTR sequences of ADH1C, ATP13A3, EIF4G1, FBXO7, GBA+GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PARK2, PARK7, PINK1, PLA2G6, SNCA, UCHL1, and VPS35genes were tested with a massive parallel sequencing method using Ion Torrent technology and confirmed by Sanger sequencing. Variants were acquired by Next Generation Sequencing Ion Torrent workflow. Potential candidate haplotypes were assessed using filtering from a manually created matrix. We compared this haplotype frequency with population data from the 1000 Genome Project (1000GP).

Results: The co-occurence of 4 intron variants (rs11564187, rs36220738, rs200829235, rs3789329) and 1 exon variant (rs33995883) were identified in LRRK2 gene in 6 probands; none of these variants was found in controls. The intron variants occurred almost exclusively together with the exon variant; which means that the variants should be in the haplotype. A comparison with 1000GP data revealed significant differences in haplotype frequencies between the patients and 1000GP “controls”. A risk ratio of 6.5 and an odds ratio of 7.45 were estimated using 1000GP data with the assumption that the population risk of PD is 1%.

Conclusion: Based on data of  1000 Genomes project, the frequency of the shared occurence of these variants in the population is almost exclusive, so we assume that these variants are in haplotype. Therefore, they may be associated with Parkinson´s disease and may be one of the causes of the increased prevalence of parkinsonism in the investigated isolated region.
This study was supported by MH CZ – DRO (FNOl, 00098892, by the European regional Development Fund-Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868) and by IGA LF 2020-017.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-variants-of-the-lrrk2-gene-in-the-haplotype-as-one-of-the-potential-risk-factors-for-endemic-parkinsonism-in-a-small-isolated-region-in-the-czech-republic/