{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:32:33Z","timestamp":1787506353422,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2026,7]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n SRRM4<\/jats:italic>\n is an exclusively neural\u2010expressed splicing\u2010factor gene not yet associated with a monogenic condition.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n We sought to delineate movement disorders caused by\n SRRM4<\/jats:italic>\n variants. De novo splice\u2010donor\u2010site variants at position +2 of intron 5 of\n SRRM4<\/jats:italic>\n (c.464+2T>C, c.464+2T>A) occurred in three unrelated patients with dystonia and chorea. We present detailed phenotypic information on these individuals and characterize the effect of the splice\u2010site alteration.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Exome and genome sequencing were used to identify\n SRRM4<\/jats:italic>\n variants. To assess the consequence of a mutant +2 residue at the affected splice donor of\n SRRM4<\/jats:italic>\n , we performed transcriptomic analyses using short\u2010read and long\u2010read RNA\u2010sequencing in patient fibroblasts in which\n SRRM4<\/jats:italic>\n expression was induced by genome editing.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Clinical presentations were characterized by infantile combined dystonic and choreatic syndromes or chorea\u2010predominant disease. Studies in\n SRRM4<\/jats:italic>\n expression\u2010activated cells revealed two variant\u2010specific\n SRRM4<\/jats:italic>\n \u2010mRNA isoforms including one that was characterized by a 69\u2010nucleotide in\u2010frame insertion without creation of a premature termination codon, suggestive of a mechanism other than loss\u2010of\u2010function. Additionally, we uncovered altered splicing patterns of known\n SRRM4<\/jats:italic>\n downstream mRNA\u2010substrates in patient cells compared to\n SRRM4<\/jats:italic>\n expression\u2010activated control fibroblasts, such as a conserved\n AP1S2<\/jats:italic>\n microexon.\n AP1S2<\/jats:italic>\n is linked to a monogenic syndrome with abnormal movements and missplicing of its microexon is a well\u2010established outcome in neural models of\n SRRM4<\/jats:italic>\n disruption.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n We conclude that the patients' phenotypes are caused by a previously undiagnosed\n SRRM4<\/jats:italic>\n \u2010related disorder, offering a basis for improved understanding of mechanistic convergence in genetic movement disorders and potential therapeutic targeting of the misregulated splicing events. \u00a9 2026 The Author(s).\n Movement Disorders<\/jats:italic>\n published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mds.70297","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:27:31Z","timestamp":1775802451000},"page":"1704-1715","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator\n \n SRRM4<\/i>\n <\/scp>"],"prefix":"10.1002","volume":"41","author":[{"given":"Philip","family":"Harrer","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health Technical University of Munich Munich Germany"},{"name":"Institute of Neurogenomics Helmholtz Zentrum M\u00fcnchen Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Kittke","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health Technical 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Christoph","family":"Korenke","sequence":"additional","affiliation":[{"name":"Department of Neuropaediatric and Metabolic Diseases University Children's Hospital Oldenburg Oldenburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-9153","authenticated-orcid":false,"given":"Michael","family":"Zech","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health Technical University of Munich Munich Germany"},{"name":"Institute of Neurogenomics Helmholtz Zentrum M\u00fcnchen Munich Germany"},{"name":"Institute for Advanced Study Technical University of Munich Garching 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