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There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society. Show less

Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels. Show less

Restless legs syndrome (RLS) is a frequent neurological disorder which is presented in idiopathic and secondary form. Idiopathic RLS is associated with common genetic variants in four chromosomal regions. Recently, multiple sclerosis (MS) was identified as a common cause for secondary RLS. The aim of our study was to evaluate the prevalence of RLS among Czech patients with MS and to further analyze the impact of known genetic risk factors for RLS in patients with MS. Each patient underwent a semi-structured interview. A patient was considered to be affected by RLS if all four standard criteria had ever been met in their lifetime. The sample was genotyped using 12 single nucleotide polymorphisms within the four genomic regions, which were selected according to the results of previous genome-wide association studies. A total of 765 subjects with MS were included in the study and the diagnosis of RLS was confirmed in 245 subjects (32.1%, 95%CI 28.7-35.4%). The genetic association study included 642 subjects; 203 MS patients with RLS were compared to 438 MS patients without RLS. No significant association with MEIS 1, BTBD9, and PTPRD gene variants was found despite sufficient statistical power for the first two loci. There was a trend for association with the MAP2K5/SCOR1 gene - the best model for the risk allele was the recessive one (p nominal=0.0029, p corrected for four loci and two models=0.023, odds ratio=1.60). We confirmed that RLS prevalence was high in patients with multiple sclerosis, but this form did not share all genetic risk variants with idiopathic RLS. Show less

Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q. Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms. We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p = 1.26 x 10(-5), odds ratio (OR) = 1.47, rs3923809 in BTBD9, p = 4.11 x 10(-5), OR = 1.58 and rs6494696 in MAP2K5/LBXCOR1, p = 0.04764, OR = 1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9. Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering. Show less