{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T12:11:49Z","timestamp":1777983109705,"version":"3.51.4"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T00:00:00Z","timestamp":1607990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Dutch Organization for Health Research and Development","award":["917-86-319"],"award-info":[{"award-number":["917-86-319"]}]},{"name":"Dutch Organization for Health Research and Development","award":["912-12-109"],"award-info":[{"award-number":["912-12-109"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM 117177"],"award-info":[{"award-number":["R01 GM 117177"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa270","type":"journal-article","created":{"date-parts":[[2020,12,19]],"date-time":"2020-12-19T07:52:36Z","timestamp":1608364356000},"page":"3892-3899","source":"Crossref","is-referenced-by-count":17,"title":["<i>De Novo<\/i> variants in <i>EEF2<\/i> cause a neurodevelopmental disorder with benign external hydrocephalus"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9472-6050","authenticated-orcid":false,"given":"Maria J","family":"Nabais S\u00e1","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, 6525 GA Nijmegen, The Netherlands"},{"name":"Unit for Multidisciplinary Research in Biomedicine, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar\/Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Alexandra N","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA"}]},{"given":"Grace","family":"Yoon","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics and Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada"}]},{"given":"Graeme A M","family":"Nimmo","sequence":"additional","affiliation":[{"name":"Fred A Litwin Family Centre for Genetic Medicine, University Health Network\/Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada"}]},{"given":"Christopher M","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Chicago, Chicago, IL 60637, USA"}]},{"given":"Mich\u00e8l A","family":"Willemsen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, Amalia Children\u2019s Hospital, 6525 GA Nijmegen, The Netherlands"}]},{"given":"Francisca","family":"Millan","sequence":"additional","affiliation":[{"name":"GeneDx, Gaithersburg, MD 20877, USA"}]},{"given":"Alexandra","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA"}]},{"given":"Rolph","family":"Pfundt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, 6525 GA Nijmegen, The Netherlands"}]},{"given":"Arjan P M","family":"de Brouwer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, 6525 GA Nijmegen, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2402-9698","authenticated-orcid":false,"given":"Jonathan D","family":"Dinman","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0000-2917","authenticated-orcid":false,"given":"Bert B A","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, 6525 GA Nijmegen, The Netherlands"}]}],"member":"286","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"2021022609385671500_ref1","doi-asserted-by":"crossref","first-page":"a032649","DOI":"10.1101\/cshperspect.a032649","article-title":"Translation elongation and recoding in eukaryotes","volume":"10","author":"Dever","year":"2018","journal-title":"Cold Spring Harb. 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Crystallogr."},{"key":"2021022609385671500_ref9","doi-asserted-by":"crossref","first-page":"13497","DOI":"10.1016\/S0021-9258(17)36859-X","article-title":"Elongation factor 2 mutants deficient in diphthamide formation show temperature-sensitive cell growth","volume":"269","author":"Kimata","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2021022609385671500_ref10","doi-asserted-by":"crossref","first-page":"32639","DOI":"10.1074\/jbc.M607076200","article-title":"Translation elongation factor 2 anticodon mimicry domain mutants affect fidelity and diphtheria toxin resistance","volume":"281","author":"Ortiz","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021022609385671500_ref11","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3109\/10409230903307311","article-title":"The A-Z of bacterial translation inhibitors","volume":"44","author":"Wilson","year":"2009","journal-title":"Crit. Rev. Biochem. Mol. 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Mutat."},{"key":"2021022609385671500_ref19","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/gim.2015.148","article-title":"Clinical application of whole-exome sequencing across clinical indications","volume":"18","author":"Retterer","year":"2016","journal-title":"Genet. Med."},{"key":"2021022609385671500_ref20","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1002\/humu.22450","article-title":"A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases","volume":"34","author":"Neveling","year":"2013","journal-title":"Hum. 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