{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:11:18Z","timestamp":1760832678546,"version":"build-2065373602"},"reference-count":19,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2020,5,23]],"date-time":"2020-05-23T00:00:00Z","timestamp":1590192000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["Practical Research Projects for Rare\/Intractable D"],"award-info":[{"award-number":["Practical Research Projects for Rare\/Intractable D"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["Research on Intractable Diseases"],"award-info":[{"award-number":["Research on Intractable Diseases"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Scientific Research (C)"],"award-info":[{"award-number":["Scientific Research (C)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2020,4,20]]},"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:p>Silver-Russell syndrome (SRS) is a representative imprinting disorder. A major cause is the loss of methylation (LOM) of imprinting control region 1 (ICR1) within the <jats:italic>IGF2\/H19<\/jats:italic> domain. ICR1 is a gametic differentially methylated region (DMR) consisting of two repeat blocks, with each block including three CTCF target sites (CTSs). ICR1-LOM on the paternal allele allows CTCF to bind to CTSs, resulting in <jats:italic>IGF2<\/jats:italic> repression on the paternal allele and biallelic expression of <jats:italic>H19<\/jats:italic>. We analysed 10 differentially methylated sites (DMSs) (ie, seven CTSs and three somatic DMRs within the <jats:italic>IGF2\/H19<\/jats:italic> domain, including two <jats:italic>IGF2<\/jats:italic>-DMRs and the <jats:italic>H19<\/jats:italic>-promoter) in five SRS patients with ICR1-LOM. Four patients showed consistent hypomethylation at all DMSs; however, one exhibited a peculiar LOM pattern, showing LOM at the centromeric region of the <jats:italic>IGF2<\/jats:italic>\/<jats:italic>H19<\/jats:italic> domain but normal methylation at the telomeric region. This raised important points: there may be a separate regulation of DNA methylation for the two repeat blocks within ICR1; there is independent control of somatic DMRs under each repeat block; sufficient <jats:italic>IGF2<\/jats:italic> repression to cause SRS phenotypes occurs by LOM only in the centromeric block; and the need for simultaneous methylation analysis of several DMSs in both blocks for a correct molecular diagnosis.<\/jats:p>","DOI":"10.1136\/jmedgenet-2020-106907","type":"journal-article","created":{"date-parts":[[2020,5,23]],"date-time":"2020-05-23T17:22:03Z","timestamp":1590254523000},"page":"422-425","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome"],"prefix":"10.1136","volume":"58","author":[{"given":"Ken","family":"Higashimoto","sequence":"first","affiliation":[{"name":"Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hijiri","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Amakusa Medical Center, Amakusa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Tanoue","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidefumi","family":"Tonoki","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Department of Pediatrics, Tenshi Hospital, Sapporo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoharu","family":"Tokutomi","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, School of Medicine, Iwate Medical University, Morioka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Hara","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitomi","family":"Yatsuki","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5076-6563","authenticated-orcid":false,"given":"Hidenobu","family":"Soejima","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2020,5,23]]},"reference":[{"key":"2025101722073175000_58.6.422.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2016.138"},{"key":"2025101722073175000_58.6.422.2","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2013.51"},{"key":"2025101722073175000_58.6.422.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0092-0"},{"key":"2025101722073175000_58.6.422.4","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu290"},{"key":"2025101722073175000_58.6.422.5","doi-asserted-by":"crossref","DOI":"10.1186\/s13148-016-0215-4","article-title":"Kaiso mediates human ICR1 methylation maintenance and H19 transcriptional fine regulation","volume":"8","author":"Bohne","year":"2016","journal-title":"Clin Epigenetics"},{"key":"2025101722073175000_58.6.422.6","doi-asserted-by":"crossref","DOI":"10.1186\/s13148-018-0454-7","article-title":"Is ZFP57 binding to H19\/IGF2:IG-DMR affected in Silver-Russell syndrome?","volume":"10","author":"Sparago","year":"2018","journal-title":"Clin Epigenetics"},{"key":"2025101722073175000_58.6.422.7","doi-asserted-by":"crossref","DOI":"10.1186\/s13148-019-0629-x","article-title":"Novel familial distal imprinting centre 1 (11p15.5) deletion provides further insights in imprinting regulation","volume":"11","author":"Kraft","year":"2019","journal-title":"Clin Epigenetics"},{"key":"2025101722073175000_58.6.422.8","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101321"},{"key":"2025101722073175000_58.6.422.9","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp549"},{"key":"2025101722073175000_58.6.422.10","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12318"},{"key":"2025101722073175000_58.6.422.11","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/s10038-019-0634-0","article-title":"The extent of DNA methylation anticipation due to a genetic defect in ICR1 in Beckwith-Wiedemann syndrome","volume":"64","author":"Sun","year":"2019","journal-title":"J Hum Genet"},{"key":"2025101722073175000_58.6.422.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2008.08.014"},{"key":"2025101722073175000_58.6.422.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.08.032"},{"key":"2025101722073175000_58.6.422.14","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102732"},{"key":"2025101722073175000_58.6.422.15","doi-asserted-by":"crossref","DOI":"10.1186\/s13148-018-0578-9","article-title":"Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer","volume":"10","author":"Hidaka","year":"2018","journal-title":"Clin Epigenetics"},{"key":"2025101722073175000_58.6.422.16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s13258-013-0079-3","article-title":"Novel mutations of CDKN1C in Japanese patients with Beckwith-Wiedemann syndrome","volume":"35","author":"Yatsuki","year":"2013","journal-title":"Genes Genomics"},{"key":"2025101722073175000_58.6.422.17","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3032"},{"key":"2025101722073175000_58.6.422.18","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg022"},{"key":"2025101722073175000_58.6.422.19","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr018"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmedgenet-2020-106907","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T05:07:38Z","timestamp":1760764058000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmedgenet-2020-106907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,23]]},"references-count":19,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,5,21]]},"published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1136\/jmedgenet-2020-106907"],"URL":"https:\/\/doi.org\/10.1136\/jmedgenet-2020-106907","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"type":"print","value":"0022-2593"},{"type":"electronic","value":"1468-6244"}],"subject":[],"published":{"date-parts":[[2020,5,23]]}}}