Objective: To assess the genetic background in the pedigrees with identified autosomal-dominant inheritance of parkinsonism.

Background: Increased prevalence of parkinsonism with cognitive deterioration was detected in a small  region of  south-eastern Czech Republic. Three large pedigrees with probable  autosomal-dominant inheritance patterns of parkinsonism were identified.

Methods: Molecular genetic examinations were performed in 12 clinically positive probands.  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. In total,   93 % of gene sequences were covered. Variants were  filtered using parameter MAF˂0.01. SIFT;   PolyPhen-2 prediction software was used for missense variants evaluation. PhyloP algorithm was used to assess the phylogenetical conservation.

Results: 31 rare heterozygous variants have been identified. The most interesting variants (PhyloP score ≥2 and/or missense variants) included: one variant located in coding sequence – c.143C>T in ADH1C gene, one variant in coding sequence –  c.689A>G in MAPT gene, one variant in UTR-3 region sequence – c.*77G>T in SNCA gene, one variant in exon – c.1180C>T in PARK2 gene, one variant in coding sequence – c.344A>T in PINK1 gene, three exon variants – c.2167A>G, c.6241A>G, c.4541G>A in LRRK2 gene, one variant in noncoding sequence –  c.*1593G>A and one in coding sequence – c.3662C>T in GIGYF2 gene, one exon variant – c.1027C>T in PLA2G6 gene and one variant in noncoding – c.-109G>A and one in coding sequence – c.3706C>G in EIF4G1 gene.

Conclusions: It seems that several molecular-genetic factors  play  role in the genetic background of this newly detected atypical familial neurodegenerative parkinsonism.

Supported by AZV- Ministry of Health of the Czech Republic grant Nr. 15-32715A and the MH CZ – DRO (FNOL 00098892) – 2016.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-identification-of-molecular-genetic-background-of-familial-atypical-parkinsonism-in-hornacko-a-specific-region-of-the-south-eastern-moravia-czech-republic/