{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T09:15:20Z","timestamp":1760346920349,"version":"3.40.5"},"reference-count":14,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T00:00:00Z","timestamp":1595548800000},"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":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Missense variants in <jats:italic>TUBB3<\/jats:italic> have historically been associated with either congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or malformations of cortical development (MCD). Until a recent report identified two amino acid substitutions in four patients that had clinical features of both disorders, pathogenic variants of <jats:italic>TUBB3<\/jats:italic> were thought distinct to either respective disorder. Three recurrent <jats:italic>de novo<\/jats:italic> Gly71Arg TUBB3 substitutions and a single patient with a <jats:italic>de novo<\/jats:italic> Gly98Ser substitution blurred the MCD and CFEOM3 phenotypic distinctions. Here we report a second patient with a missense c.292G&gt;A (p.Gly98Ser) substitution, but without CFEOM3, the first reported evidence that even the same TUBB3 substitution can produce a spectrum of <jats:italic>TUBB3<\/jats:italic> syndrome phenotypes. Our patient presented with amblyopia, exotropia, optic disc pallor, and developmental delay. Neuroimaging identified hypoplasia of the corpus callosum, interdigitation of the frontal lobe gyri, and dysplasia or hypoplasia of the optic nerves, basal ganglia, brainstem, and cerebellum. This report identifies the TUBB3 Gly98Ser substitution to be recurrent but inconsistently including CFEOM3, and identifies the absence of joint contractures and the presence of optic disc abnormalities that may be genotype\u2010specific to the TUBB3 Gly98Ser substitution.<\/jats:p>","DOI":"10.1002\/ajmg.a.61747","type":"journal-article","created":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T07:03:44Z","timestamp":1595574224000},"page":"2161-2167","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The recurrent <scp>TUBB3 Gly98Ser<\/scp> substitution is the first described to inconsistently result in <scp>CFEOM3<\/scp>"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2938-6202","authenticated-orcid":false,"given":"Scott C.","family":"Smith","sequence":"first","affiliation":[{"name":"Human Genetics Laboratory Munroe\u2010Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann Haskins","family":"Olney","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine Munroe\u2010Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Beavers","sequence":"additional","affiliation":[{"name":"Department of Radiology Children's Hospital, University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Spaulding","sequence":"additional","affiliation":[{"name":"Human Genetics Laboratory Munroe\u2010Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilu","family":"Nelson","sequence":"additional","affiliation":[{"name":"Human Genetics Laboratory Munroe\u2010Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelly","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine Munroe\u2010Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4576-025X","authenticated-orcid":false,"given":"Jennifer N.","family":"Sanmann","sequence":"additional","affiliation":[{"name":"Human Genetics Laboratory Munroe\u2010Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center  Omaha Nebraska 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