Objective: To report the genetic results of genotyping and whole-exome sequencing (WES) data of patients with Parkinson’s disease (PD) from the Central European countries of the Visegrad group (V4: Czech Republic, Hungary, Poland and Slovakia).To report the genetic results of genotyping and whole-exome sequencing (WES) data of patients with Parkinson’s disease (PD) from the Central European countries of the Visegrad group (V4: Czech Republic, Hungary, Poland and Slovakia).

Background: Little is known about the genetic profile of monogenic PD in the V4 countries, as genetic research is lagging behind that of Northwestern Europe and North America. Thus leaving patients and families with inadequate diagnoses, and without access to clinical trials, and potential treatments [1].

Method: PD patients (n=1601) were recruited within the CEGEMOD consortium as described elsewhere [2]. Genotyping data (GSA array v.3.; n=1601) were first screened for all pathogenic, likely pathogenic or risk variants within the PD-related genes [3]. Patients with negative genotyping results, young onset (age at onset <50) and/or positive family history were selected for additional whole-exome sequencing (WES; n=219) analysis. All identified variants were validated with Sanger sequencing.

Results: Using genotyping data, we identified a likely pathogenic or pathogenic POLG1 mutation in 1 PD patient (hom. p.Gly1051Arg),  and 1 patient with ATP1A3 (het p.Glu324Gly) 139 patients carried GBA1 risk variant (1 het p.Arg398Ter; 5 het p.Gly416Ser; 19 het p.Asn409Ser; 34 het p.Glu365Lys; 77 het and 3 hom p.Thr408Met) and LRRK2 were identified in 4 patients (all het p.Gly2019Ser). Leveraging the WES data of previously negative cases yielded 4 additional LRRK2-PD carriers (1 het p.Asn1437Ser; 3 het p.L1795F), 1 PRKN PD case (hom p.Arg42Pro), 2 patients carrying 2 POLG1 variants (2 het p.Pro587Leu/p.Thr251Ile) and 2 patients positive for GBA1 risk variants (1 het p.Leu483Pro; 1 het p.Thr362Ile).

Conclusion: Overall, the genotyping data identified 145 (9.1%) PD patients carrying a pathogenic, likely pathogenic or risk variant within the PD-related genes. WES analysis identified an additional 9 PD cases, increasing the total yield to 154 (9.62%). Further large-scale genetic studies using targeted and untargeted approaches are urgently needed to investigate the pathogenic role of novel genes and variants specific to this region.

References: References:
1. Skorvanek, M. et al. LRRK2 mutations in Parkinson’s disease patients from Central Europe: A case control study. Parkinsonism Relat. Disord. 83, 110–112 (2021).
2. Ostrozovicova, M. et al. Central European Group on Genetics of Movement Disorders. Eur. J. Neurol. 31, e16165 (2024).
3. Blauwendraat, C., Nalls, M. A. & Singleton, A. B. The genetic architecture of Parkinson’s disease. Lancet Neurol. 19, 170–178 (2020).

Funding sources:
This study was funded by the Slovak Grant and Development Agency under contracts APVV-22-0279 and by the EU Renewal and Resilience Plan “Large projects for excellent researchers” under grant No. 09I03-03-V03-00007.

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