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Biomarkers of dystonia are notoriously lacking.<\/jats:p><jats:p>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 1\u00d7 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.<\/jats:p><jats:p>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)\u2014being lower in samples with late or incomplete penetrance\u2014thus 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.<\/jats:p>","DOI":"10.1093\/brain\/awab360","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T13:49:44Z","timestamp":1632404984000},"page":"644-654","source":"Crossref","is-referenced-by-count":44,"title":["Blood DNA methylation provides an accurate biomarker of<i>KMT2B<\/i>-related dystonia and predicts onset"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0836-8267","authenticated-orcid":false,"given":"Nazanin","family":"Mirza-Schreiber","sequence":"first","affiliation":[{"name":"Institute of Neurogenomics (ING), Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"},{"name":"Neurogenetic Systems Analysis Group, Institute of Neurogenomics (ING), Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zech","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics (ING), Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"},{"name":"Institute of Human Genetics, Technical University of Munich, School of Medicine, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory","family":"Wilson","sequence":"additional","affiliation":[{"name":"Research Unit Molecular Epidemiology, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Brunet","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics (ING), Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"},{"name":"Institute of Human Genetics, Technical University of Munich, School of Medicine, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-8823","authenticated-orcid":false,"given":"Matias","family":"Wagner","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics (ING), Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"},{"name":"Institute of Human Genetics, Technical University of Munich, School of Medicine, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Jech","sequence":"additional","affiliation":[{"name":"Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, 121 08 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Boesch","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medizinische Universit\u00e4t, 6020 Insbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matej","family":"\u0160korv\u00e1nek","sequence":"additional","affiliation":[{"name":"Department of Neurology, P. 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