Journal Article

DZNE-2024-00310

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

Thomsen, M. ; Marth, K. ; Loens, S. ; Everding, J. ; Junker, J. ; Borngräber, F. ; Ott, F. ; Jesús, S. ; Gelderblom, M. ; Odorfer, T. ; Kuhlenbäumer, G. ; Kim, H.-J. ; Schaeffer, E. ; Becktepe, J. ; Kasten, M. ; Brüggemann, N. ; Pfister, R. ; Kollewe, K. ; Krauss, J. K. ; Lohmann, E.DZNE* ; Hinrichs, F. ; Berg, D. ; Jeon, B. ; Busch, H. ; Altenmüller, E. ; Mir, P. ; Kamm, C. ; Volkmann, J. ; Zittel, S. ; Ferbert, A. ; Zeuner, K. E. ; Rolfs, A. ; Bauer, P. ; Kühn, A.Extern* ; Bäumer, T. ; Klein, C. ; Lohmann, K.

2024
Wiley New York, NY

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Please use a persistent id in citations: doi:10.1002/mds.29693

Abstract: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD).To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes.We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature.We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic.This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keyword(s): Humans (MeSH) ; Dystonia: genetics (MeSH) ; Dystonic Disorders: genetics (MeSH) ; Mutation: genetics (MeSH) ; Gene Frequency (MeSH) ; Parkinson Disease: genetics (MeSH) ; Molecular Chaperones: genetics (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Apoptosis Regulatory Proteins: genetics (MeSH) ; GCH1 ; GNAL ; KMT2B ; PRKRA ; SGCE ; THAP1 ; TOR1A ; dystonia ; monogenic ; primary dystonia ; TOR1A protein, human ; Molecular Chaperones ; THAP1 protein, human ; DNA-Binding Proteins ; Apoptosis Regulatory Proteins

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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