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

Clinical Epigenetics

Ralitza H. Gavrilova¹  Rory J. Olson¹  Laura Schultz-Rogers¹  Giovanna S. Zorzi²  Serena Galosi³  Vincenzo Leuzzi³  Paola Soliveri⁴  Matteo Garibaldi⁵  Alessandro Capuano⁶  Aidin Foroutan⁷  Bekim Sadikovic⁸  Marco Andreani⁹  Lucia Pedace⁹  Evelina Miele⁹  Marcello Niceta^1,10  Andrea Ciolfi^1,10  Simone Pizzi^1,10  Lorena Travaglini^1,10  Marco Tartaglia^1,10  Paolo Prontera^1,11  Maria Francesca Bedeschi^1,12  Maria Iascone^1,13  Barbara M. Garavaglia^1,14  Chiara Reale^1,14  Celeste Panteghini^1,14  Federica Invernizzi^1,14  Emanuele Agolini^1,15 

[1] Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA;Department of Child Neurology, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy;Department of Human Neuroscience, Child Neurology and Psychiatry, Sapienza University, Rome, Italy;Department of Neurology, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy;Department of Neuroscience, NESMOS, Sapienza University, Sant’Andrea Hospital, Rome, Italy;Department of Neuroscience, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;Department of Pathology and Laboratory Medicine, Western University, N6A 3K7, London, ON, Canada;Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Canada;Department of Pathology and Laboratory Medicine, Western University, N6A 3K7, London, ON, Canada;Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Canada;Molecular Diagnostics Division, London Health Sciences Centre, London, Canada;Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy;Maternal-Infantile Department, University Hospital of Perugia, Perugia, Italy;Medical Genetic Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy;Medical Genetics Laboratory, ASST Papa Giovanni XXIII, Bergamo, Italy;Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy;Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;

关键词: DNA methylation;    Episignature;    KMT2B;    Dystonia 28;   

DOI  :  10.1186/s13148-021-01145-y

来源: Springer

【 摘 要 】

BackgroundDystonia 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.ResultsWe 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.ConclusionsWe 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.

【 授权许可】

CC BY