Objective: The aim of the study was to identify shared genetic variants potentially associated with familial neurodegenerative parkinsonism using whole-exome analysis.

Background: Increased prevalence of neurodegenerative parkinsonism with familial aggregation has been described in a small isolated region in the Czech Republic. The obtained pedigree included 8 generations.

Method: NGS Ion AmpliSeq Exome method (IonTorrent) was used for five subfamily trios. Each trio comprised of two affected and one healthy person. DNA exome libraries were sequenced on IonPI chips. Variants were predicted using pipeline Torrent Suite/Ingenuity Variant Analysis/ Two case/control analysis. Final filtering was done with respect to population frequency (Global MAF˂1%), variant effects and biological context (parkinsonism responsible genes). Last filter was done with respect to the segregation of the disease within particular subfamily. Almost whole exome was sequenced with coverage 1-20 and 90 % of exome was covered more than 20x in all samples. Together more than 70.000 variants with average base coverage depth 75 were analyzable in all trios before filtering.

Results: There were found no one founder pathogenic variant in the subfamilies through the pedigree. Each subfamily trio shows different set of suspected variants. Trio A shares 2 variants with trio D (novel variant NM_002386.3:c.322G>A;p.A108T in the gene MC1R/RP11-566K11.2 and rare variant NM_015210.3:c.1445C>T;p.A482V in the gene MTCL1 ), Trio B shares 1 rare variant with trio C (NM_001256864.1:c.1817A>C;p.H606P in the gene DNAJC6). In addition, in trios C and E there were found two novel gene CSMD1 variants NM_033225.5:c.3335A>G,p.E1112G and c.4071C>G; p.I1357M respectively.

Conclusion: It can be concluded that the genetic basis of this hereditary parkinsonism is likely to be heterogeneous. Assessment of the functional effect of these variants using specific cell lines in combination with targeted mutagenesis is ongoing
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/whole-exome-trio-analysis-in-isolated-population-of-southeast-moravia-czech-republic-with-familial-parkinsonism-suggests-its-heterogeneous-genetic-background/