{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T03:14:05Z","timestamp":1785899645840,"version":"3.56.0"},"reference-count":64,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:00Z","timestamp":1760140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2021-12374963"],"award-info":[{"award-number":["RF-2021-12374963"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Dominantly acting variants in TUBB2B have primarily been associated with cortical dysplasia complex with other brain malformations 7 (CDCBM7), a disorder in which cortical brain abnormalities are typically linked to developmental delay\/intellectual disability (DD\/ID) and seizures. While the majority of TUBB2B pathogenic variants have been linked to isolated CDCBM7, only one family with CDCBM7 and congenital fibrosis of the extraocular muscles (CFEOM) has been reported so far. We describe a second individual with a severe phenotype of CFEOM combined with CDCBM7 carrying a pathogenic TUBB2B missense variant previously reported in two individuals with isolated CDCBM7. Methods: A trio-based WGS analysis was performed. The structural impact of the identified substitution was assessed by using the UCSF Chimera (v.1.17.3) software and PyMOL docking plugin DockingPie tool. Results: WGS analysis identified a de novo missense TUBB2B variant (p.Ile202Thr, NM_178012.5), previously associated with isolated CDCBM7. Structural analysis and docking simulations revealed that Ile202 contributes to establishing a proper hydrophobic environment required to stabilize GTP\/GDP in the \u03b2-tubulin pocket. p.Ile202Thr was predicted to disrupt these interactions. Conclusions: Our findings broaden the mutational spectrum of TUBB2B-related CFEOM, targeting a different functional domain of the protein, and further document the occurrence of phenotypic heterogeneity. We also highlight the limitations of exome sequencing in accurately mapping TUBB2B coding exons due to its high sequence homology with TUBB2A and suggest targeted or genome analyses when clinical suspicion is strong.<\/jats:p>","DOI":"10.3390\/genes16101182","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T08:10:31Z","timestamp":1760343031000},"page":"1182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The p.Ile202Thr Substitution in TUBB2B Can Be Associated with Syndromic Presentation of Congenital Fibrosis of the Extraocular Muscles"],"prefix":"10.3390","volume":"16","author":[{"given":"Cecilia","family":"Mancini","sequence":"first","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Chiriatti","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bruselles","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"D\u2019ambrosio","sequence":"additional","affiliation":[{"name":"Medical and Molecular Genetics, AORN A. Cardarelli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ciolfi","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9883-311X","authenticated-orcid":false,"given":"Marco","family":"Ferilli","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"},{"name":"Department of Computer, Control and Management Engineering, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Cappelletti","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University \u201cTor Vergata\u201d, 00173 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4584-0663","authenticated-orcid":false,"given":"Mattia","family":"Carvetta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"},{"name":"Department of Biochemical Sciences \u201cAlessandro Rossi Fanelli\u201d, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-8018","authenticated-orcid":false,"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Cordeddu","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4766-7753","authenticated-orcid":false,"given":"Marcello","family":"Niceta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Parrino","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Capolino","sequence":"additional","affiliation":[{"name":"Rare Diseases and Medical Genetics Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Mamm\u00ec","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, GOM Bianchi-Melacrino-Morelli, 89124 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana","family":"Senese","sequence":"additional","affiliation":[{"name":"Department of Advanced Diagnostic and Therapeutic Technologies, AORN A. Cardarelli Hospital, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Muto","sequence":"additional","affiliation":[{"name":"Department of Advanced Diagnostic and Therapeutic Technologies, AORN A. Cardarelli Hospital, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4815-9550","authenticated-orcid":false,"given":"Manuela","family":"Priolo","sequence":"additional","affiliation":[{"name":"Medical and Molecular Genetics, AORN A. Cardarelli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,11]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Tubulinopathies Overview. GeneReviews, University of Washington."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.semcdb.2022.07.009","article-title":"Tubulin Mutations in Human Neurodevelopmental Disorders","volume":"137","author":"Maillard","year":"2023","journal-title":"Semin. Cell Dev. 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