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Mirza-Schreiber, N. ; Zech, M. ; Wilson, R. ; Brunet, T. ; Wagner, M. ; Jech, R.* ; Boesch, S.* ; Škorvánek, M.* ; Necpál, J.* ; Weise, D.* ; Weber, S. ; Mollenhauer, B.* ; Trenkwalder, C.* ; Maier, E.M.* ; Borggraefe, I.* ; Vill, K.* ; Hackenberg, A.* ; Pilshofer, V.* ; Kotzaeridou, U.* ; Schwaibold, E.M.C.* ; Hoefele, J.* ; Waldenberger, M. ; Gieger, C. ; Peters, A. ; Meitinger, T.* ; Schormair, B.* ; Winkelmann, J. ; Oexle, K.

Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.

Brain, DOI: 10.1093/brain/awab360 (2021)
Publ. Version/Full Text Postprint Research data DOI PMC
Open Access Green
Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1x log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (p = 0.003) - being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Kmt2b ; Age At Onset ; Dystonia ; Episignature ; Mode Of Inheritance; Kmt2b; Classification; Episignatures; Diagnosis
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Journal Brain: A Journal of Neurology
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Institute of Epidemiology (EPI)
Grants Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
European Reference Network for Rare Neurological Diseases
Technische Universitat Munchen, Munich, Germany
Helmholtz Zentrum Munchen, Munich, Germany
Charles University, Prague, Czech Republic
Czech Ministry of Education
European Joint Programme on Rare Diseases (EJP RD COFUND-EJP)
Slovak Grant and Development Agency
Operational Programme Integrated Infrastructure - ERDF
Helmholtz Zentrum MunchenGerman Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
State of Bavaria
German Research Foundation