{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:37:10Z","timestamp":1787017030505,"version":"build-2736575974"},"reference-count":31,"publisher":"BMJ","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PNRR-MR1-2023-12377314"],"award-info":[{"award-number":["PNRR-MR1-2023-12377314"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,8,3]]},"abstract":"<jats:p>\n                    <jats:italic>RNU4ATAC<\/jats:italic>\n                    is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic\n                    <jats:italic>RNU4ATAC<\/jats:italic>\n                    pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the \u2018molar tooth sign\u2019 (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.\n                  <\/jats:p>\n                  <jats:p>\n                    We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four\n                    <jats:italic>RNU4ATAC<\/jats:italic>\n                    variants (n.16G&gt;A, n.51G&gt;A, n.13C&gt;T and n.30G&gt;A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and\n                    <jats:italic>RNU4ATAC<\/jats:italic>\n                    -related skeletal disorders.\n                  <\/jats:p>\n                  <jats:p>\n                    These findings expand the phenotypic spectrum of\n                    <jats:italic>RNU4ATAC<\/jats:italic>\n                    -related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.\n                  <\/jats:p>","DOI":"10.1136\/jmg-2025-110987","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T17:20:19Z","timestamp":1757611219000},"page":"jmg-2025-110987","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Further evidence of\n                    <i>RNU4ATAC<\/i>\n                    variants causing Joubert syndrome with skeletal involvement"],"prefix":"10.1136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2470-665X","authenticated-orcid":false,"given":"Fulvio","family":"D\u2019Abrusco","sequence":"first","affiliation":[{"name":"Neurogenetics Research Centre, IRCCS Mondino Foundation, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Gana","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Centre, IRCCS Mondino Foundation, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Alfei","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Ospedale dei Bambini Vittore Buzzi, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Scarano","sequence":"additional","affiliation":[{"name":"Pediatric Unit, IRCCS University Hospital of Bologna Sant Orsola Polyclinic, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-821X","authenticated-orcid":false,"given":"Francesco","family":"Nicita","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, IRCCS Bambino Ges\u00f9 Childrens' Hospital, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9276-4590","authenticated-orcid":false,"given":"Enrico Silvio","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, IRCCS Bambino Ges\u00f9 Childrens' Hospital, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Digilio","sequence":"additional","affiliation":[{"name":"Rare Diseases and Medical Genetics Unit, IRCCS Bambino Ges\u00f9 Childrens' Hospital, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginevra","family":"Zanni","sequence":"additional","affiliation":[{"name":"Rare Diseases and Medical Genetics Unit, IRCCS Bambino Ges\u00f9 Childrens' Hospital, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Barbuti","sequence":"additional","affiliation":[{"name":"Imaging Department, IRCCS Bambino Ges\u00f9 Childrens' Hospital, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Carlicchi","sequence":"additional","affiliation":[{"name":"Pediatric Radiology Unit, Vittore Buzzi Children\u2019s Hospital, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pichiecchio","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy"},{"name":"Neuroradiology Department, Foundation National Neurological Institute Casimiro Mondino, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5188-9418","authenticated-orcid":false,"given":"Stefano","family":"D\u2019Arrigo","sequence":"additional","affiliation":[{"name":"Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-0066","authenticated-orcid":false,"given":"Valentina","family":"Serpieri","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0600-6820","authenticated-orcid":false,"given":"Enza Maria","family":"Valente","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Centre, IRCCS Mondino Foundation, Pavia, Italy"},{"name":"Department of Molecular Medicine, University of Pavia, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"2025091110201354000_jmg-2025-110987v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61399"},{"key":"2025091110201354000_jmg-2025-110987v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-121321-093528"},{"key":"2025091110201354000_jmg-2025-110987v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31963"},{"key":"2025091110201354000_jmg-2025-110987v1.4","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-103832"},{"key":"2025091110201354000_jmg-2025-110987v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.11.019"},{"key":"2025091110201354000_jmg-2025-110987v1.6","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1002\/ajmg.a.33416","article-title":"Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic 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Dominant variants in major spliceosome u4 and u5 small nuclear rna genes cause neurodevelopmental disorders through splicing disruption. 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