{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T23:48:36Z","timestamp":1773272916134,"version":"3.50.1"},"reference-count":47,"publisher":"Cold Spring Harbor Laboratory","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:p>Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes <jats:italic>EZH2<\/jats:italic> and <jats:italic>NSD1<\/jats:italic>, which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase (<jats:italic>DNMT3A<\/jats:italic>) gene that results in Tatton-Brown\u2013Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in <jats:italic>EZH2<\/jats:italic> (c.2050C&gt;T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including <jats:italic>DNMT3A<\/jats:italic>) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for <jats:italic>DNMT3A<\/jats:italic>, the co-occurrence of a duplication involving this gene and a pathogenic alteration in <jats:italic>EZH2<\/jats:italic> in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.<\/jats:p>","DOI":"10.1101\/mcs.a002899","type":"journal-article","created":{"date-parts":[[2018,5,25]],"date-time":"2018-05-25T16:40:15Z","timestamp":1527266415000},"page":"a002899","source":"Crossref","is-referenced-by-count":9,"title":["Co-occurrence of a maternally inherited <i>DNMT3A<\/i> duplication and a paternally inherited pathogenic variant in <i>EZH2<\/i> in a child with growth retardation and severe short stature: atypical Weaver syndrome or evidence of a <i>DNMT3A<\/i> dosage effect?"],"prefix":"10.1101","volume":"4","author":[{"given":"Katarzyna","family":"Polonis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick R.","family":"Blackburn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raul A.","family":"Urrutia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gwen A.","family":"Lomberk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Kruisselbrink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margot A.","family":"Cousin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole J.","family":"Boczek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole L.","family":"Hoppman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dusica","family":"Babovic-Vuksanovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric W.","family":"Klee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel N.","family":"Pichurin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"246","published-online":{"date-parts":[[2018,5,25]]},"reference":[{"key":"2021112506154119000_4.4.a002899.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084147"},{"key":"2021112506154119000_4.4.a002899.2","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/ajmg.a.33244","article-title":"Acute lymphoblastic leukemia in Weaver syndrome","volume":"152A","year":"2010","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.3","doi-asserted-by":"publisher","DOI":"10.1101\/gr.190629.115"},{"key":"2021112506154119000_4.4.a002899.4","first-page":"1789","article-title":"Further phenotype description, genotype characterization in patients with de novo interstitial deletion on 2p23.2-24.1","volume":"164A","year":"2014","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2540"},{"key":"2021112506154119000_4.4.a002899.6","first-page":"1594","article-title":"Molecular cytogenetic analysis of de novo dup(5)(q35.2q35.3) and review of the literature of pure partial trisomy 5q","volume":"140","year":"2006","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.7","doi-asserted-by":"crossref","first-page":"10207","DOI":"10.1038\/ncomms10207","article-title":"NSD1 mutations generate a genome-wide DNA methylation signature","volume":"6","year":"2015","journal-title":"Nat Commun"},{"key":"2021112506154119000_4.4.a002899.8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/1755-8794-6-35","article-title":"Genomic pathway analysis reveals that EZH2 and HDAC4 represent mutually exclusive epigenetic pathways across human cancers","volume":"6","year":"2013","journal-title":"BMC Med Genomics"},{"key":"2021112506154119000_4.4.a002899.9","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1002\/humu.22946","article-title":"Weaver syndrome\u2013associated EZH2 protein variants show impaired histone methyltransferase function in vitro","volume":"37","year":"2016","journal-title":"Hum Mutat"},{"key":"2021112506154119000_4.4.a002899.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.089433"},{"key":"2021112506154119000_4.4.a002899.11","first-page":"2158","article-title":"The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1: is it really a reversed Sotos syndrome?","volume":"161A","year":"2013","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.12","doi-asserted-by":"publisher","DOI":"10.1038\/ng.621"},{"key":"2021112506154119000_4.4.a002899.13","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-090613-094245"},{"key":"2021112506154119000_4.4.a002899.14","doi-asserted-by":"publisher","DOI":"10.2337\/db06-0214"},{"key":"2021112506154119000_4.4.a002899.15","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/oby.2003.89","article-title":"Sequence variants of the POMC gene and their associations with body composition in children","volume":"11","year":"2003","journal-title":"Obes Res"},{"key":"2021112506154119000_4.4.a002899.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2007.12.011"},{"key":"2021112506154119000_4.4.a002899.17","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.164"},{"key":"2021112506154119000_4.4.a002899.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2006.10.002"},{"key":"2021112506154119000_4.4.a002899.19","doi-asserted-by":"crossref","first-page":"101","DOI":"10.6065\/apem.2013.18.3.101","article-title":"Genetic syndromes associated with overgrowth in childhood","volume":"18","year":"2013","journal-title":"Ann Pediatr Endocrinol Metab"},{"key":"2021112506154119000_4.4.a002899.20","doi-asserted-by":"publisher","DOI":"10.1038\/509"},{"key":"2021112506154119000_4.4.a002899.21","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30064"},{"key":"2021112506154119000_4.4.a002899.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.01.006"},{"key":"2021112506154119000_4.4.a002899.23","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102402"},{"key":"2021112506154119000_4.4.a002899.24","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.112"},{"key":"2021112506154119000_4.4.a002899.25","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2435"},{"key":"2021112506154119000_4.4.a002899.26","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2436"},{"key":"2021112506154119000_4.4.a002899.27","first-page":"2084","article-title":"Defining the phenotype associated with microduplication reciprocal to Sotos syndrome microdeletion","volume":"164A","year":"2014","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.28","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/ajmg.a.37588","article-title":"Tatton-Brown\u2013Rahman syndrome due to 2p23 microdeletion","volume":"170","year":"2016","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.29","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19981002)79:4<294::AID-AJMG12>3.0.CO;2-M"},{"key":"2021112506154119000_4.4.a002899.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2014.02.007"},{"key":"2021112506154119000_4.4.a002899.31","first-page":"247","article-title":"Further evidence of contrasting phenotypes caused by reciprocal deletions and duplications: duplication of NSD1 causes growth retardation and microcephaly","volume":"3","year":"2013","journal-title":"Mol Syndromol"},{"key":"2021112506154119000_4.4.a002899.32","doi-asserted-by":"publisher","DOI":"10.4161\/epi.4.6.9392"},{"key":"2021112506154119000_4.4.a002899.33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/cge.12803","article-title":"NSD1 duplication in Silver\u2013Russell syndrome (SRS): molecular karyotyping in patients with SRS features","volume":"91","year":"2017","journal-title":"Clin Genet"},{"key":"2021112506154119000_4.4.a002899.34","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/ajmg.a.34427","article-title":"A de novo interstitial deletion of 2p23.3-24.3 in a boy presenting with intellectual disability, overgrowth, dysmorphic features, skeletal myopathy, dilated cardiomyopathy","volume":"158A","year":"2012","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2008.07.010"},{"key":"2021112506154119000_4.4.a002899.36","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1002\/ajmg.a.38356","article-title":"The phenotype of EZH2 haploinsufficiency-1.2-Mb deletion at 7q36.1 in a child with tall stature and intellectual disability","volume":"173","year":"2017","journal-title":"Am J Med Genet A"},{"key":"2021112506154119000_4.4.a002899.37","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.385"},{"key":"2021112506154119000_4.4.a002899.38","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36229"},{"key":"2021112506154119000_4.4.a002899.39","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2917"},{"key":"2021112506154119000_4.4.a002899.40","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.ajhg.2017.03.010","article-title":"Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability","volume":"100","year":"2017","journal-title":"Am J Hum Genet"},{"key":"2021112506154119000_4.4.a002899.41","doi-asserted-by":"publisher","DOI":"10.1038\/nature04431"},{"key":"2021112506154119000_4.4.a002899.42","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1002\/pd.2319","article-title":"Genetic considerations in the prenatal diagnosis of overgrowth syndromes","volume":"29","year":"2009","journal-title":"Prenat Diagn"},{"key":"2021112506154119000_4.4.a002899.43","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3274"},{"key":"2021112506154119000_4.4.a002899.44","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/cge.12878","article-title":"Novel DNMT3A germline mutations are associated with inherited Tatton-Brown\u2013Rahman syndrome","volume":"91","year":"2017","journal-title":"Clin Genet"},{"key":"2021112506154119000_4.4.a002899.45","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306555"},{"key":"2021112506154119000_4.4.a002899.46","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.194027"},{"key":"2021112506154119000_4.4.a002899.47","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33769"}],"container-title":["Molecular Case Studies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/mcs.a002899","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T14:15:59Z","timestamp":1637849759000},"score":1,"resource":{"primary":{"URL":"http:\/\/molecularcasestudies.cshlp.org\/lookup\/doi\/10.1101\/mcs.a002899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,25]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,8,1]]},"published-print":{"date-parts":[[2018,8]]}},"alternative-id":["10.1101\/mcs.a002899"],"URL":"https:\/\/doi.org\/10.1101\/mcs.a002899","relation":{},"ISSN":["2373-2865","2373-2873"],"issn-type":[{"value":"2373-2865","type":"print"},{"value":"2373-2873","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,25]]}}}