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 1× 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.

Chair of Epidemiology Institute for Medical Information Processing Biometry and Epidemiology Medical Faculty Ludwig Maximilians Universität München 81377 Munich Germany

Chair of Neurogenetics Technical University of Munich School of Medicine 81675 Munich Germany

Department of Child Neurology and Metabolic Medicine Center for Pediatric and Adolescent Medicine University Hospital Heidelberg 69120 Heidelberg Germany

Department of Neurology Asklepios Fachklinikum Stadtroda 07646 Stadtroda Germany

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague 121 08 Prague Czech Republic

Department of Neurology Medizinische Universität 6020 Insbruck Austria

Department of Neurology P J Safarik University 04011 Kosice Slovakia

Department of Neurology University Hospital L Pasteur 04011 Kosice Slovakia

Department of Neurology University of Leipzig 04103 Leipzig Germany

Department of Neurology Zvolen Hospital 96001 Zvolen Slovakia

Department of Pediatric Neurology University Children's Hospital 8032 Zürich Switzerland

Dr von Hauner Children's Hospital Ludwig Maximilians University 80337 Munich Germany

German Center for Diabetes Research 85764 Neuherberg Germany

Institute of Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Institute of Human Genetics Heidelberg University 69120 Heidelberg Germany

Institute of Human Genetics Technical University of Munich School of Medicine 81675 Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Munich Cluster for Systems Neurology 81377 Munich Germany

Neurogenetic Systems Analysis Group Institute of Neurogenomics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Ordensklinikum Linz Barmherzige Schwestern 4010 Linz Austria

Research Unit Molecular Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

University Medical Center Goettingen Department of Neurology Paracelsus Elena Klinik 34128 Kassel Germany

Mov Disord. 2022 Jan;37(1):38. doi: 10.1002/mds.28877. PubMed

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Episignature analysis of moderate effects and mosaics