{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:22:27Z","timestamp":1790306547513,"version":"4.1.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by the premature closure of the coronal sutures, dysmorphic facial features and limb anomalies, is caused by haploinsufficiency of <jats:italic>TWIST1<\/jats:italic>. Although the majority of variants localize in the coding region of the gene, two variants in the 5\u2032 UTR have been recently reported to generate novel upstream initiation codons.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Skeletal dysplasia Next-generation sequencing (NGS) panel was used for genetic analysis in a patient with bicoronal synostosis, facial dysmorphisms and limb anomalies. The variant pathogenicity was assessed by a luciferase reporter promoter assay.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Here, we describe the identification of a third ATG-creating <jats:italic>de novo<\/jats:italic> variant, c.-18C&amp;gt;T, in the 5\u2032 UTR of <jats:italic>TWIST1<\/jats:italic> in the patient with a clinical diagnosis of Saethre-Chotzen syndrome. It was predicted to create an out-of-frame new upstream translation initiation codon resulting in a 40 amino acid larger functionally inactive protein. We performed luciferase reporter promoter assays to demonstrate that the variant does indeed reduce translation from the main open reading frame.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> This is the third variant identified in this region and confirms the introduction of upstream ATGs in the 5\u2032 UTR of <jats:italic>TWIST1<\/jats:italic> as a pathogenic mechanism in Saethre-Chotzen syndrome. This case report shows the necessity for performing functional characterization of variants of unknown significance within national health services.<\/jats:p>","DOI":"10.3389\/fgene.2022.1089417","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T08:08:29Z","timestamp":1672819709000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Case report: A third variant in the 5\u2032 UTR of TWIST1 creates a novel upstream translation initiation site in a child with Saethre-Chotzen syndrome"],"prefix":"10.3389","volume":"13","author":[{"given":"Francisca","family":"Diaz-Gonzalez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier M.","family":"Sacedo-Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R. 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