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The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive.<\/jats:p>\n                  <jats:p>Here, we analysed blood and fibroblast DNA methylation, transcriptomes, proteomes and phenotypes of 53 MORC2 patients.<\/jats:p>\n                  <jats:p>We identified a MORC2-specific DNA methylation episignature that is universal across all MORC2-associated phenotypes and conserved across different tissues. The MORC2 episignature consists mainly of DNA hypermethylation in promoter regions, leading to transcriptional repression of target genes resulting in a MORC2-specific RNA signature. Concomitant downregulation of three disease-associated genes\u2014ERCC8, NDUFAF2 and FKTN\u2014at different levels mirrors the variable biochemical defects and clinical manifestations observed in MORC2 patients. Silencing of NDUFAF2 accounts for the Leigh syndrome manifestation, whereas dysmorphic features are due to the repression of ERCC8.<\/jats:p>\n                  <jats:p>Overall, we showed that pathogenic MORC2 variants cause specific episignature, whereby methylation level variability and its repression impact on target genes explains the pleiotropy and predicts phenotypic heterogeneity in MORC2-related disorders. We predict that epigenetic variation may underlie pleiotropy in other Mendelian disorders.<\/jats:p>","DOI":"10.1093\/brain\/awaf159","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T07:56:08Z","timestamp":1745826968000},"page":"163-177","source":"Crossref","is-referenced-by-count":6,"title":["Pleiotropic effects of\n                    <i>MORC2<\/i>\n                    derive from its epigenetic signature"],"prefix":"10.1093","volume":"149","author":[{"given":"Fatemeh","family":"Peymani","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Ebihara","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitrii","family":"Smirnov","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kopajtich","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Ando","sequence":"additional","affiliation":[{"name":"Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences , Kagoshima 890-8544 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9276-4590","authenticated-orcid":false,"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Neuromuscular Disorders Research Unit, Bambino Ges\u00f9 Children's Hospital IRCCS , Rome 00165 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3327-4054","authenticated-orcid":false,"given":"Rosalba","family":"Carrozzo","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , Rome 00165 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Diodato","sequence":"additional","affiliation":[{"name":"Neuromuscular Disorders Research Unit, Bambino Ges\u00f9 Children's Hospital IRCCS , Rome 00165 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-3738","authenticated-orcid":false,"given":"Felix","family":"Distelmaier","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University , Beijing 100005 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-3766","authenticated-orcid":false,"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta , Milano 20133 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Hempel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Heidelberg University , Heidelberg 69120 ,","place":["Germany"]},{"name":"Institute of Human Genetics, University Hospital Heidelberg , Heidelberg 69120 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Iwanicka-Pronicka","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children's Memorial Health Institute , Warsaw 04-730 ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[{"name":"Department of Neurology, Friedrich-Baur-Institute, LMU University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) M\u00fcnchen , Munich 81377 ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE) , Munich 81377 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L","family":"Stenton","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Lamperti","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta , Milano 20133 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University , Beijing 100005 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysylu","family":"Murtazina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , Moscow 115522 ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences , Kagoshima 890-8544 ,","place":["Japan"]},{"name":"Department of Physical Therapy, Kagoshima University of School of Health Sciences , Kagoshima 890-8544 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University , Tokyo 113-8421 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Piekutowska-Abramczuk","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children's Memorial Health Institute , Warsaw 04-730 ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0589-0703","authenticated-orcid":false,"given":"Agn\u00e9s","family":"R\u00f6tig","sequence":"additional","affiliation":[{"name":"UMR1163, Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, Institut Imagine , Paris 75015 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oxana","family":"Ryzhkova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , Moscow 115522 ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schlein","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , Hamburg 20246 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Shagina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , Moscow 115522 ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Takashima","sequence":"additional","affiliation":[{"name":"Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences , Kagoshima 890-8544 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina","family":"Tsygankova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , Moscow 115522 ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zech","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Meitinger","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Shimura","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Munich , Neuherberg 85764 ,","place":["Germany"]},{"name":"Department of Metabolism, Chiba Children's Hospital , Chiba City 266-0007 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3923-8636","authenticated-orcid":false,"given":"Kei","family":"Murayama","sequence":"additional","affiliation":[{"name":"Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University , Tokyo 113-8421 ,","place":["Japan"]},{"name":"Department of Metabolism, Chiba Children's Hospital , Chiba City 266-0007 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