{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T08:53:40Z","timestamp":1769849620698,"version":"3.49.0"},"reference-count":9,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Rothmund\u2013Thomson syndrome (RTS) is an ultra\u2010rare, genetically heterogeneous autosomal recessive genodermatosis characterized by poikiloderma, sparse hair and eyebrows, photosensitivity, and short stature. The recently described RTS type 4 (RTS\u20104), caused by biallelic variants in the\n                    <jats:italic>DNA2<\/jats:italic>\n                    gene, is associated with additional distinctive features such as microphthalmia, corneal opacity, congenital cataracts (rather than juvenile), and hypothyroidism. To date, eight individuals with RTS\u20104 have been reported, all carrying a deep intronic variant in\n                    <jats:italic>DNA2<\/jats:italic>\n                    (ENST00000358410.8:c.588\u20102214A&gt;G) and originating from Brazilian or Portuguese ethnic backgrounds. We present the first patient with RTS\u20104 outside these ethnic backgrounds, harboring the same deep intronic\n                    <jats:italic>DNA2<\/jats:italic>\n                    variant (ENST00000358410.8:c.588\u20102214A&gt;G) in combination with a novel pathogenic variant (ENST00000358410.8:c.2519\u2009T&gt;C, Leu840Pro). This patient expands the molecular spectrum of RTS\u20104 and underscores the critical role of genome sequencing in identifying pathogenic deep intronic variants. Additionally, the patient's response to recombinant human growth hormone treatment is described. Finally, this patient, undiagnosed for several years, was solved through an international effort at the 2024 Undiagnosed Hackathon, highlighting the value of international cooperation and resource sharing toward ensuring that no patient remains undiagnosed.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.64179","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T13:13:51Z","timestamp":1753190031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Undiagnosed Hackathon Ends Diagnostic Odyssey in a Patient With\n                    <scp>\n                      <i>DNA2<\/i>\n                    <\/scp>\n                    \u2010Related Rothmund\u2013Thomson Syndrome"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-2132","authenticated-orcid":false,"given":"Beril","family":"Ay","sequence":"first","affiliation":[{"name":"School of Medicine, Acibadem Mehmet Ali Aydinlar University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8310-4053","authenticated-orcid":false,"given":"Ozlem","family":"Akgun\u2010Dogan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Department of Pediatrics, School of Medicine Acibadem Mehmet Ali Aydinlar University  Istanbul Turkey"},{"name":"Acibadem Mehmet Ali Aydinlar University Rare Diseases and Orphan Drugs Application and Research Center (ACURARE)  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-0235","authenticated-orcid":false,"given":"Fulya","family":"Taylan","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institutet  Stockholm Sweden"},{"name":"Clinical Genetics and Genomics Karolinska University Hospital  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Marcelis","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6552-2801","authenticated-orcid":false,"given":"Saygin","family":"Abali","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, School of Medicine Acibadem Mehmet Ali Aydinlar University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3253-2768","authenticated-orcid":false,"given":"Jiin Ying","family":"Lim","sequence":"additional","affiliation":[{"name":"Genetics Service, Department of Paediatrics KK Women's and Children's Hospital  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"May Christine","family":"Malicdan","sequence":"additional","affiliation":[{"name":"National Institutes of Health, Undiagnosed Diseases Program, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5522-3418","authenticated-orcid":false,"given":"Helene","family":"Cederroth","sequence":"additional","affiliation":[{"name":"Wilhelm Foundation  Brottby Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0295-5545","authenticated-orcid":false,"given":"Mikk","family":"Cederroth","sequence":"additional","affiliation":[{"name":"Wilhelm Foundation  Brottby Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5322-7116","authenticated-orcid":false,"given":"Lorenzo D.","family":"Botto","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics University of Utah  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0683-9731","authenticated-orcid":false,"given":"Yasemin","family":"Alanay","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Department of Pediatrics, School of Medicine Acibadem Mehmet Ali Aydinlar University  Istanbul Turkey"},{"name":"Acibadem Mehmet Ali Aydinlar University Rare Diseases and Orphan Drugs Application and Research Center (ACURARE)  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01941-1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2022-109119"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01834-08"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2023.1296409"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/ijd.15498"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-2046"},{"key":"e_1_2_8_8_1","volume-title":"Rothmund\u2010Thomson Syndrome","author":"Wang L. L.","year":"1993"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.06.009"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1101"}],"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.64179","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T02:23:42Z","timestamp":1766975022000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.64179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":9,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/ajmg.a.64179"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.64179","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,22]]},"assertion":[{"value":"2025-03-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e64179"}}