{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:17:47Z","timestamp":1791371867317,"version":"4.3.1"},"reference-count":17,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T00:00:00Z","timestamp":1741564800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Sotos syndrome is a rare genetic disorder characterized by distinctive facial features, including a broad and prominent forehead, dolichocephaly, and learning disabilities ranging from mild to severe intellectual impairment. Affected individuals often show overgrowth in height and head circumference over two standard deviations. The syndrome is caused by haploinsufficiency of the <jats:italic>NSD1<\/jats:italic> gene, with no evidence of genetic heterogeneity to date. Here we describe the unsolved case of a child of 4\u2009years of age with a clinical diagnosis of Sotos syndrome. However, trio exome sequencing (ES) and exon chromosomal microarray (CMA) analysis excluded both small and large mutations in the <jats:italic>NSD1<\/jats:italic> gene. As part of the Telethon Undiagnosed Programme, we used additional tools to investigate the possibility of new genes or elusive mutations that may have been missed by previous molecular diagnostic approaches. Therefore, we performed Nanopore long\u2010read sequencing. This revealed a 447\u2009bp insertion in exon 13 of the <jats:italic>NSD1<\/jats:italic> gene. mRNA analysis confirmed in\u2010frame skipping of exon 13 that encodes for two PHD domains. The genomic insertion shows 100% identity with an intronic region, although inverted, containing an <jats:italic>AluSx1<\/jats:italic> element 2\u2009kb upstream of the skipped exon, which may drive the event by masking the splice acceptor site of exon 13. Interestingly, this is the first case of Sotos syndrome linked to a pathogenic mechanism involving an insertion enclosing a transposable element generating a protein devoid of two PHDs, which are required for reading histone post\u2010translational modifications.<\/jats:p>","DOI":"10.1002\/ajmg.a.64039","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T01:06:18Z","timestamp":1741741578000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nanopore Sequencing Solves an Elusive Case of Sotos Syndrome"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0214-8004","authenticated-orcid":false,"given":"Pasquale","family":"Di Letto","sequence":"first","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Budillon","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"},{"name":"Department of Medicine University of Trieste, Surgery and Health Science  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Iffat","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Del Vecchio Blanco","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3750-1592","authenticated-orcid":false,"given":"Mariateresa","family":"Zanobio","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7367-7911","authenticated-orcid":false,"given":"Margherita","family":"Scarpato","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Onore","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-125X","authenticated-orcid":false,"given":"Giulio","family":"Piluso","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"TUDP Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"},{"name":"Telethon Institute of Genetics and Medicine  Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioacchino","family":"Scarano","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli,\u201d Monaldi Hospital  Naples Italy"},{"name":"Medical Genetics Unit, AORN \u201cSan Pio,\u201d, Hospital \u201cG. Rummo\u201d  Benevento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalaura","family":"Torella","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"},{"name":"Telethon Institute of Genetics and Medicine  Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2010.111"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20102\u201036"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12111736"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.1999.2864"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.40.110405.090448"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010024\u201001177\u20103"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000204"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010016\u20100974\u20104"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2018.04.064"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1086"},{"key":"e_1_2_11_14_1","first-page":"1993","volume-title":"Sotos Syndrome","author":"Tatton\u2010Brown K.","year":"2004"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201686"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/life11090877"},{"issue":"1","key":"e_1_2_11_17_1","first-page":"1","article-title":"The First Japanese Familial Sotos Syndrome With a Novel Mutation of the NSD1 Gene","volume":"52","author":"Tei S.","year":"2006","journal-title":"Kobe Journal of Medical Sciences"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119241"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.64039","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T04:32:40Z","timestamp":1749184360000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.64039"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,10]]},"references-count":17,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1002\/ajmg.a.64039"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.64039","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,10]]},"assertion":[{"value":"2024-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e64039"}}