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Variants in the translational regulator <jats:italic>EIF2AK2<\/jats:italic> were first linked to neurodevelopmental\u2010delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in <jats:italic>EIF4A2<\/jats:italic>, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We sought to characterize the role of <jats:italic>EIF4A2<\/jats:italic> variants in dystonic conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We undertook an unbiased search for likely deleterious variants in mutation\u2010constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for <jats:italic>EIF4A2<\/jats:italic> variants. Western blotting and immunocytochemical studies were performed in patient\u2010derived fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We report the discovery of a novel heterozygous <jats:italic>EIF4A2<\/jats:italic> frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence\u2010 to adulthood\u2010onset dystonia with tremor. In patient\u2010derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4\u2010Not, the complex that interacts with eIF4A2 to mediate microRNA\u2010dependent translational repression. By complementing the analyses with fibroblasts bearing <jats:italic>EIF4A2<\/jats:italic> biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4\u2010Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified <jats:italic>EIF4A2<\/jats:italic> deletion variants (c.470_472del, c.1144_1145del) in another two dystonia\u2010affected pedigrees.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate that <jats:italic>EIF4A2<\/jats:italic> haploinsufficiency underlies a previously unrecognized dominant dystonia\u2010tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later\u2010onset dystonic conditions. \u00a9 2023 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.29562","type":"journal-article","created":{"date-parts":[[2023,7,23]],"date-time":"2023-07-23T05:29:46Z","timestamp":1690090186000},"page":"1914-1924","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Dystonia Linked to <scp><i>EIF4A2<\/i><\/scp> Haploinsufficiency: A Disorder of Protein Translation Dysfunction"],"prefix":"10.1002","volume":"38","author":[{"given":"Philip","family":"Harrer","sequence":"first","affiliation":[{"name":"Institute of Neurogenomics Helmholtz Zentrum M\u00fcnchen  Munich Germany"},{"name":"Institute of Human Genetics, School of Medicine Technical University of Munich  Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5497-8715","authenticated-orcid":false,"given":"Matej","family":"\u0160korv\u00e1nek","sequence":"additional","affiliation":[{"name":"Department of Neurology P.J. 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