Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile

Andrea Ciolfi, Aidin Foroutan, Alessandro Capuano, Lucia Pedace, Lorena Travaglini, Simone Pizzi, Marco Andreani, Evelina Miele, Federica Invernizzi, Chiara Reale, Celeste Panteghini, Maria Iascone, Marcello Niceta, Ralitza H. Gavrilova, Laura Schultz-Rogers, Emanuele Agolini, Maria Francesca Bedeschi, Paolo Prontera, Matteo Garibaldi, Serena GalosiVincenzo Leuzzi, Paola Soliveri, Rory J. Olson, Giovanna S. Zorzi, Barbara M. Garavaglia, Marco Tartaglia, Bekim Sadikovic

Research output: Contribution to journalArticlepeer-review


Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the “episignature” associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.

Original languageEnglish (US)
Article number157
JournalClinical Epigenetics
Issue number1
StatePublished - Dec 2021


  • DNA methylation
  • Dystonia 28
  • Episignature
  • KMT2B

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)


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