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Keywords: Neurogenetics; Neurodegeneration; Exome sequencing; Rare variants; Brain/nervous system

R. Vodicka 1; R. Vrtel 1; K. Kolarikova 1; K. Mensikova 2; P. Kanovsky 2; J. Stellmachova 1; M. Prochazka 1

1) Institute of Medical Genetics, University Hospital, Olomouc, Czech Republic; 2) Department of Neurology, Faculty of Medicine and Dentistry, Palacky University, University Hospital, Olomouc, Czech Republic

We described higher prevalence of parkinsonism in the small isolated southeastern Moravian region in the Czech Republic and in addition with well assembled eleven generation large pedigree.
The study aims to set proper and accessible subfamily trios from the pedigree to find shared genetic variants potentially associated with parkinsonism using whole exome analyses.
We used NGS Ion AmpliSeq Exome method (IonTorrent) 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.
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.
It can be concluded that genetic contribution to the disease in our large pedigree could be heterogeneous. Detailed whole exome analyses in genetically isolated parkinsonism patients could contribute to further understanding of the molecular-genetic mechanism and background of the disease. This study was supported by MH CZ – DRO (FNOl, 00098892).