{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:22:49Z","timestamp":1787656969468,"version":"build-2736575974"},"reference-count":23,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF\u20102019\u201012370059"],"award-info":[{"award-number":["RF\u20102019\u201012370059"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015694","name":"Fondazione Cassa di Risparmio di Firenze","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015694","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["DN. 1553 11.10.2022"],"award-info":[{"award-number":["DN. 1553 11.10.2022"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Most pathogenic tubulin variants arise\n                    <jats:italic>de novo<\/jats:italic>\n                    in sporadic patients, causing severe brain malformations and significant neurodevelopmental impairment. The resulting reproductive disadvantage typically prevents these mutations from being transmitted to offspring. While a few variants are inherited from somatic or gonadal mosaic parents, vertical transmission of constitutional variants remains rare, though increasingly documented. Here, we report the father\u2010to\u2010daughter transmission of a novel constitutional\n                    <jats:italic>TUBB<\/jats:italic>\n                    variant [NM_178014.4:c.991C&gt;T; p.(Leu331Phe)]. Both individuals presented with intellectual disability and a malformation of cortical development (MCD). To validate the pathogenicity of this variant, we performed functional and immunofluorescence assays\n                    <jats:italic>in vitro<\/jats:italic>\n                    on patient\u2010derived fibroblast cultures. These experiments supported the involvement of the variant in significantly impairing cell motility, altering cytoskeleton organization, and affecting cellular morphology. Our findings from this family, alongside literature review of constitutional and mosaic tubulinopathies, suggest that pathogenic germline\n                    <jats:italic>TUBB<\/jats:italic>\n                    variants can occasionally be inherited. Transmission is facilitated by the relatively mild clinical anatomoclinical phenotype. When a pathogenic\n                    <jats:italic>TUBB<\/jats:italic>\n                    variant is identified in an index patient, comprehensive parental clinical, neuroradiological, and genetic evaluation is crucial to accurately assess reproductive risk.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70289","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T09:51:43Z","timestamp":1787392303000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Constitutional\n                    <i>TUBB<\/i>\n                    Variant Associated With Familial Malformations of Cortical Development"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7597-940X","authenticated-orcid":false,"given":"Elena","family":"Cellini","sequence":"first","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6790-6251","authenticated-orcid":false,"given":"Davide","family":"Mei","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Cavallin","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0933-6120","authenticated-orcid":false,"given":"Simona","family":"Fiori","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"},{"name":"Department of Neuroscience, Pharmacology and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1839-9788","authenticated-orcid":false,"given":"Luciana","family":"Tramacere","sequence":"additional","affiliation":[{"name":"USL Toscana Centro, Neurology Unit San Giovanni di Dio Hospital  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4599-4083","authenticated-orcid":false,"given":"Maria Elena","family":"Melica","sequence":"additional","affiliation":[{"name":"Nephrology and Dialysis Unit Meyer Children's Hospital IRCCS  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2555-2130","authenticated-orcid":false,"given":"Giulia","family":"Antonelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2272-8973","authenticated-orcid":false,"given":"Simona","family":"Vird\u00f2","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8933-7694","authenticated-orcid":false,"given":"Elena","family":"Parrini","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-7079","authenticated-orcid":false,"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"},{"name":"Department of Neuroscience, Pharmacology and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010611"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu082"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jdn.10284"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6715"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.11.017"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds393"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-019-0335-3"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.40503"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13232"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2025.06.003"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10588"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.26140"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.10.014"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31821043f5"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26196"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2022.07.009"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv250"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2613"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq377"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.03.018"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.12.011"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab052"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcae118"}],"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.70289","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.70289","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70289","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:01:30Z","timestamp":1787655690000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.70289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,22]]},"references-count":23,"alternative-id":["10.1002\/ajmg.a.70289"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.70289","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,22]]},"assertion":[{"value":"2026-02-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ajmg.a.70289"}}