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Zech, M. ; Boesch, S.* ; Škorvánek, M.* ; Necpál, J.* ; Švantnerová, J.* ; Wagner, M. ; Dincer, Y.* ; Sadr-Nabavi, A.* ; Serranová, T.* ; Rektorová, I.* ; Havránková, P.* ; Ganai, S.* ; Mosejová, A.* ; Příhodová, I.* ; Šarláková, J.* ; Kulcsarová, K.* ; Ulmanová, O.* ; Bechyně, K.* ; Ostrozovičová, M.* ; Haň, V.* ; Ventosa, J.R.* ; Shariati, M.* ; Shoeibi, A.* ; Weber, S. ; Mollenhauer, B.* ; Trenkwalder, C.* ; Berutti, R. ; Strom, T.M.* ; Ceballos-Baumann, A.* ; Mall, V.* ; Haslinger, B.* ; Jech, R.* ; Winkelmann, J.

Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.

Parkinsonism Relat. Disord. 84, 129-134 (2021)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. Results: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. Conclusions: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Copy-number Variant ; Diagnostic Yield ; Dystonia ; Read-depth Analysis
ISSN (print) / ISBN 1353-8020
e-ISSN 1873-5126
Journal Parkinsonism & Related Disorders
Quellenangaben Volume: 84, Issue: , Pages: 129-134 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants internal research program at Helmholtz Zentrum Munchen, Munich, Germany ("Physician Scientists for Groundbreaking Projects")
Technische Universitat Munchen, Munich, Germany
Helmholtz Zentrum Munchen, Munich, Germany
Charles University, Prague, Czech Republic
Czech Ministry of Education
Czech Ministry of Education under EJP RD
European Joint Programme on Rare Diseases (EJP RD COFUND-EJP)
Slovak Grant and Development Agency
Operational Programme Integrated Infrastructure - ERDF
Else Kroner-Fresenius-Stiftung