{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:34:23Z","timestamp":1791045263861,"version":"4.1.0"},"reference-count":9,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Rubinstein\u2013Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder linked to haploinsufficiency of\n                    <jats:italic>CREBBP<\/jats:italic>\n                    (RSTS1) and\n                    <jats:italic>EP300<\/jats:italic>\n                    (RSTS2) genes. Characteristic features often include distinctive facial traits, broad thumbs and toes, short stature, and various degrees of intellectual disability. The clinical presentation of RSTS is notably variable, making it challenging to establish a clear genotype\u2013phenotype correlation, except for specific variants which cause the allelic Menke\u2013Hennekam syndrome. Trio exome analysis, data collection via networking and GeneMatcher platforms, transcript processing analysis, and DNA methylation profiling were performed. We identified two unrelated patients with de novo variants in\n                    <jats:italic>EP300<\/jats:italic>\n                    (NM_001429.4: c.3671+5G&gt;C; c.3671+5_3671+8delGTAA) predicted to cause in\u2010frame exon 20 skipping, confirmed in one patient. In silico 3D protein modeling suggested that exon 20 deletion (comprising 27 amino acids) likely alters the structural conformation between the RING_CBP\u2010p300 and HAT\u2010KAT11 domains. Clinically, both patients displayed severe RSTS2\u2010like clinical features, including autism spectrum disorder, speech delay, hearing loss, microcephaly, developmental delay, and intellectual disability, alongside ocular, respiratory, and cardiovascular abnormalities. Additionally, one patient developed early\u2010onset colorectal cancer. DNA methylation profiling in Subject #1 confirmed RSTS but did not align with the specific episignatures for RSTS1 or RSTS2. We propose that skipping of exon 20 in\n                    <jats:italic>EP300<\/jats:italic>\n                    is associated with a distinct form of Rubinstein\u2013Taybi syndrome featuring clinical characteristics not fully aligning with RSTS1 or RSTS2. Our findings increase the understanding of RSTS genetic and molecular basis and stress the need for further research to establish definitive genotype\u2013phenotype correlations.\n                  <\/jats:p>","DOI":"10.1111\/cge.14654","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T20:53:32Z","timestamp":1732740812000},"page":"354-358","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Skipping of Exon 20 in\n                    <i>EP300<\/i>\n                    : A Novel Variant Linked to Rubinstein\u2013Taybi Syndrome With Atypical and Severe Clinical Manifestations"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7630-8365","authenticated-orcid":false,"given":"Lisa","family":"Pavinato","sequence":"first","affiliation":[{"name":"Institute for Oncology Research, BIOS+  Bellinzona Switzerland"},{"name":"Universit\u00e0 Della Svizzera Italiana  Lugano Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9475-6586","authenticated-orcid":false,"given":"Silvia","family":"Carestiato","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Rita Levi\u2010Montalcini University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0178-5327","authenticated-orcid":false,"given":"Slavica","family":"Trajkova","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Rita Levi\u2010Montalcini University of Turin  Turin Italy"},{"name":"Medical Genetics Unit, Citt\u00e0 Della Salute e Della Scienza University Hospital  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Sorasio","sequence":"additional","affiliation":[{"name":"Santa Croce e Carle Hospital, Pediatrics Unit  Cuneo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9065-3886","authenticated-orcid":false,"given":"Giovanna","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health University of Milan  Milano Italy"},{"name":"Endocrinology Unit, Fondazione IRCCS ca\u2019 Granda Ospedale Maggiore Policlinico  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2113-6196","authenticated-orcid":false,"given":"Luisa","family":"De Sanctis","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-6606","authenticated-orcid":false,"given":"Jennifer","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"McConkey","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre  London Ontario Canada"},{"name":"Department of Pathology and Laboratory Medicine Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Rzasa","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Todd","sequence":"additional","affiliation":[{"name":"UCHealth Adult Genetics Clinic\u2013Anschutz Medical Campus, Adult Medical Genetics Clinic  Aurora USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Balzo","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Fondazione IRCCS ca\u2019 Granda Ospedale Maggiore Policlinico  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8927-8900","authenticated-orcid":false,"given":"Simona","family":"Cardaropoli","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1556-4998","authenticated-orcid":false,"given":"Alessandro","family":"Bruselles","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore di Sanit\u00e0  Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9383-6883","authenticated-orcid":false,"given":"Silvia","family":"De Rubeis","sequence":"additional","affiliation":[{"name":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-8313","authenticated-orcid":false,"given":"Joseph D.","family":"Buxbaum","sequence":"additional","affiliation":[{"name":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children's Hospital, IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre  London Ontario Canada"},{"name":"Department of Pathology and Laboratory Medicine Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3793-5788","authenticated-orcid":false,"given":"Giovanni Battista","family":"Ferrero","sequence":"additional","affiliation":[{"name":"University of Torino Department of Clinical and Biological Sciences  Orbassano Italy"},{"name":"Medical Genetics Unit and Thalassemia Center, San Luigi University Hospital  Orbassano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8318-7231","authenticated-orcid":false,"given":"Alfredo","family":"Brusco","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Rita Levi\u2010Montalcini University of Turin  Turin Italy"},{"name":"Medical Genetics Unit, Citt\u00e0 Della Salute e Della Scienza University Hospital  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/376348a0"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1086\/429130"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2023-109438"},{"issue":"3","key":"e_1_2_9_5_1","article-title":"Menke\u2010Hennekam Syndrome; Delineation of Domain\u2010Specific Subtypes With Distinct Clinical and DNA Methylation Profiles","volume":"5","author":"Haghshenas S.","year":"2024","journal-title":"HGG Advances"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24446"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.906"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61883"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2642"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0042-0"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14654","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.14654","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14654","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:15:48Z","timestamp":1775801748000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.14654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":9,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1111\/cge.14654"],"URL":"https:\/\/doi.org\/10.1111\/cge.14654","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/CGE.14654\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14654\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14654\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14654\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14654\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14654\/v2\/decision1","asserted-by":"object"}]},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,27]]},"assertion":[{"value":"2024-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}