{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:09:55Z","timestamp":1792098595734,"version":"4.4.0"},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,7,25]],"date-time":"2017-07-25T00:00:00Z","timestamp":1500940800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>SMARCA4 chromatin remodelling factor is mutated in 11% of Coffin\u2013Siris syndrome (CSS) patients and in almost all small\u2010cell carcinoma of the ovary hypercalcaemic type (SCCOHT) tumours. Missense mutations with gain\u2010of\u2010function or dominant\u2010negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole\u2010exome sequencing to study a 15\u2010year\u2010old patient with mild CSS who concomitantly developed SCCOHT at age 13\u2009years. Interestingly, our patient also showed congenital microphthalmia, which has never previously been reported in CSS patients. We detected a <jats:italic>de novo<\/jats:italic> germline heterozygous nonsense mutation in exon 19 of <jats:italic>SMARCA4<\/jats:italic> (c.2935C\u2009&gt;\u2009T;p.Arg979*), and a somatic frameshift mutation in exon 6 (c.1236_1236delC;p.Gln413Argfs*88), causing complete loss of SMARCA4 immunostaining in the tumour. The immunohistochemical findings are supported by the observation that the c.2935C\u2009&gt;\u2009T mutant transcript was detected by reverse transcription polymerase chain reaction at a much lower level than the wild\u2010type allele in whole blood and the lymphoblastoid cell line of the proband, confirming nonsense\u2010mediated mRNA decay. Accordingly, immunoblotting demonstrated that there was approximately half the amount of SMARCA4 protein in the proband's cells as in controls. This study suggests that <jats:italic>SMARCA4<\/jats:italic> constitutional mutations associated with CSS are not necessarily non\u2010truncating, and that haploinsufficiency may explain milder CSS phenotypes, as previously reported for haploinsufficient <jats:italic>ARID1B<\/jats:italic>. In addition, our case supports the dual role of chromatin remodellers in developmental disorders and cancer, as well as the involvement of SMARCA4 in microphthalmia, confirming previous findings in mouse models and the DECIPHER database. Finally, we speculate that mild CSS might be under\u2010recognized in a proportion of SCCOHT patients harbouring <jats:italic>SMARCA4<\/jats:italic> mutations. \u00a9 2017 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4926","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T10:42:39Z","timestamp":1497350559000},"page":"9-15","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["<i>SMARCA4<\/i> inactivating mutations cause concomitant Coffin\u2013Siris syndrome, microphthalmia and small\u2010cell carcinoma of the ovary hypercalcaemic type"],"prefix":"10.1002","volume":"243","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-1988","authenticated-orcid":false,"given":"Edoardo","family":"Errichiello","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Vetro","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Dora","family":"Notarangelo","sequence":"additional","affiliation":[{"name":"Unit of Paediatric Oncology Spedali Civili di Brescia  Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"de Jonge","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berardo","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Vergani","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina Rita","family":"Giglio","sequence":"additional","affiliation":[{"name":"Department of Biomedical Experimental and Clinical Sciences \u2018Mario Serio\u2019  Florence Italy"},{"name":"Medical Genetic Unit Meyer Children's University Hospital  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Morbini","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsetta","family":"Zuffardi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,7,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2219"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35933"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22394"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12225"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36533"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-015-1535-8"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2016.03.013"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37356"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2928"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2931"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2922"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8935-3-21"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0631813100"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4585"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.10.060"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2016.12.011"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.001"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.5114\/pjp.2013.39331"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0247-4"},{"key":"e_1_2_7_21_2","article-title":"Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)","volume":"2","author":"Ramos P","year":"2014","journal-title":"Rare Dis"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2015.129"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.25279"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3399"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gore.2015.03.005"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4225"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.2350\/15-04-1624-CR.1"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-016-9957-6"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4926","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4926","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T08:56:55Z","timestamp":1760950615000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.4926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,25]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2017,9]]}},"alternative-id":["10.1002\/path.4926"],"URL":"https:\/\/doi.org\/10.1002\/path.4926","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,25]]},"assertion":[{"value":"2017-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-05-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-07-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}