{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:55:49Z","timestamp":1781067349005,"version":"3.54.1"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010434","name":"\u201cla Caixa\u201d Foundation","doi-asserted-by":"publisher","award":["LCF\/BQ\/PI21\/11830009"],"award-info":[{"award-number":["LCF\/BQ\/PI21\/11830009"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Horizon 2020","award":["84764"],"award-info":[{"award-number":["84764"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["148390"],"award-info":[{"award-number":["148390"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007680","name":"Universidad P\u00fablica de Navarra","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007680","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Familial Cancer"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>DICER1<\/jats:italic>\u00a0syndrome is an inherited condition associated with an increased risk of developing hamartomatous and neoplastic lesions in diverse organs, mainly at early ages. Germline pathogenic variants in <jats:italic>DICER1<\/jats:italic> cause this condition. Detecting a variant of uncertain significance in <jats:italic>DICER1<\/jats:italic> or finding uncommon phenotypes complicate the diagnosis and can negatively impact patient care. We present two unrelated patients suspected to have DICER1 syndrome. Both females (aged 13 and 15\u00a0years) presented with multinodular goiter (thyroid follicular nodular disease) and ovarian tumours. One was diagnosed with an ovarian Sertoli-Leydig cell tumour (SLCT) and the other, with an ovarian juvenile granulosa cell tumour, later reclassified as a retiform variant of SLCT. Genetic screening showed no germline pathogenic variants in <jats:italic>DICER1<\/jats:italic>. However, two potentially splicing variants were found, <jats:italic>DICER1<\/jats:italic> c.5365-4A&gt;G and c.5527+3A&gt;G. Also, typical somatic <jats:italic>DICER1<\/jats:italic> RNase IIIb hotspot mutations were detected in the thyroid and ovarian tissues. In silico splicing algorithms predicted altered splicing for both germline variants and skipping of exon 25 was confirmed by RNA assays for both variants. The reclassification of the ovarian tumour, leading to recognition of the association with DICER1 syndrome\u00a0and the characterization of the germline intronic variants were all applied to recently described <jats:italic>DICER1<\/jats:italic> variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls.\n<\/jats:p>","DOI":"10.1007\/s10689-023-00336-1","type":"journal-article","created":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T03:31:16Z","timestamp":1685417476000},"page":"487-493","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Reclassification of two germline DICER1 splicing variants leads to DICER1 syndrome diagnosis"],"prefix":"10.1007","volume":"22","author":[{"given":"Maria","family":"Apellaniz-Ruiz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Sabbaghian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Laure","family":"Chong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leanne","family":"de Kock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Semra","family":"Cetinkaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvan","family":"Bayramo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winand N. M.","family":"Dinjens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Glenn","family":"McCluggage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aslihan Arasli","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D.","family":"Foulkes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"336_CR1","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1002\/humu.23877","volume":"40","author":"L de Kock","year":"2019","unstructured":"de Kock L, Wu MK, Foulkes WD (2019) Ten years of DICER1 mutations: provenance, distribution, and associated phenotypes. Hum Mutat 40:1939\u20131953. https:\/\/doi.org\/10.1002\/humu.23877","journal-title":"Hum Mutat"},{"key":"336_CR2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41379-021-00905-8","volume":"35","author":"IA Gonzalez","year":"2022","unstructured":"Gonzalez IA et al (2022) DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma. Mod Pathol 35:4\u201322. https:\/\/doi.org\/10.1038\/s41379-021-00905-8","journal-title":"Mod Pathol"},{"key":"336_CR3","doi-asserted-by":"publisher","first-page":"2251","DOI":"10.1158\/1078-0432.CCR-17-3089","volume":"24","author":"KAP Schultz","year":"2018","unstructured":"Schultz KAP et al (2018) DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res 24:2251\u20132261. https:\/\/doi.org\/10.1158\/1078-0432.CCR-17-3089","journal-title":"Clin Cancer Res"},{"key":"336_CR4","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1007\/s10689-021-00264-y","volume":"20","author":"JJ Bakhuizen","year":"2021","unstructured":"Bakhuizen JJ et al (2021) Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group. Fam Cancer 20:337\u2013348. https:\/\/doi.org\/10.1007\/s10689-021-00264-y","journal-title":"Fam Cancer"},{"key":"336_CR5","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s41576-022-00556-8","volume":"24","author":"ME Rogalska","year":"2023","unstructured":"Rogalska ME, Vivori C, Valcarcel J (2022) Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects. Nat Rev Genet 24:251\u2013269. https:\/\/doi.org\/10.1038\/s41576-022-00556-8","journal-title":"Nat Rev Genet"},{"key":"336_CR6","doi-asserted-by":"publisher","unstructured":"Hatton JN et al (2023) Specifications of the ACMG\/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation. Hum Mutat vol. 2023, Article ID 9537832. https:\/\/doi.org\/10.1155\/2023\/9537832","DOI":"10.1155\/2023\/9537832"},{"key":"336_CR7","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1210\/jc.2016-2954","volume":"102","author":"NE Khan","year":"2017","unstructured":"Khan NE et al (2017) Quantification of thyroid cancer and multinodular goiter risk in the DICER1 syndrome: a family-based cohort study. 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J Pathol 230:154\u2013164. https:\/\/doi.org\/10.1002\/path.4196","journal-title":"J Pathol"},{"key":"336_CR12","doi-asserted-by":"publisher","first-page":"3637","DOI":"10.1210\/jc.2016-1328","volume":"101","author":"L de Kock","year":"2016","unstructured":"de Kock L et al (2016) Deep sequencing reveals spatially distributed distinct hot spot mutations in DICER1-related multinodular goiter. 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Approval was granted by the McGill University Faculty of Medicine Institutional Review Board (A08-M61-09B).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All participants and\/or their legal guardians provided written informed consent to participate in the study and they accepted the publication of the data.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}