{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T03:05:00Z","timestamp":1779419100934,"version":"3.53.1"},"reference-count":10,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"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"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n CSF1R<\/jats:italic>\n \u2010related disorder (\n CSF1R<\/jats:italic>\n \u2010RD) is a severe autosomal dominant leukoencephalopathy characterized by progressive cognitive, neuropsychiatric, and motor decline. Although genetic testing is widely available, numerous likely pathogenic variants in\n CSF1R<\/jats:italic>\n frequently remain classified as variants of uncertain significance (VUS), limiting the option of pre\u2010symptomatic genetic testing or prenatal options for at\u2010risk family members.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We report a male in his early 50s with progressive leukoencephalopathy and a strong multigenerational family history supported by neuropathological findings consistent with\n CSF1R<\/jats:italic>\n \u2010RD. Genetic testing identified a heterozygous\n CSF1R<\/jats:italic>\n splice\u2010region variant (c.2763\u2009+\u20094_2763\u2009+\u20097del) classified as a VUS. Targeted long\u2010read RNA sequencing of peripheral blood was performed to assess transcript\u2010level consequences.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Long\u2010read transcriptomic analysis identified a novel exon 20\u2010skipping isoform absent in pooled controls, accounting for approximately 63% of detected transcripts, with a corresponding reduction in the canonical transcript. Exon skipping (109\u2009bp) results in a frameshift and a premature termination codon in the final exon, predicted to escape nonsense\u2010mediated decay and disrupt the tyrosine kinase domain. These findings establish a direct molecular mechanism of pathogenicity. Functional evidence allowed reclassification of the variant using American College of Medical Genetics and Genomics (ACMG) and Association for Clinical Genomic Science (ACGS) guidelines from VUS to likely pathogenic, enabling definitive molecular diagnosis.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This case demonstrates that targeted long\u2010read transcriptomic sequencing can provide decisive functional evidence to resolve non\u2010canonical splice variants in\n CSF1R<\/jats:italic>\n \u2010RD. Focused transcript\u2010level assessment represents a practical adjunct to genomic testing in clinically compelling cases where DNA\u2010based interpretation alone is insufficient. \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.70366","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T02:12:21Z","timestamp":1779415941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Uncertainty to Pathogenicity: Resolving a\n \n CSF1R<\/i>\n <\/scp>\n Variant of Uncertain Significance Using Long\u2010Read Transcriptomics"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5199-7566","authenticated-orcid":false,"given":"Charles","family":"Wade","sequence":"first","affiliation":[{"name":"Department of Neuroinflammation, Queen Square Institute of Neurology University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylie","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health University College London London UK"},{"name":"Department of Neuromuscular Diseases Queen Square Institute of Neurology, University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela E.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Nottingham University Hospitals NHS Trust Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sellars","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research and Innovation Nottingham University Hospitals NHS Trust Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akram A.","family":"Hosseini","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research and Innovation Nottingham University Hospitals NHS Trust Nottingham UK"},{"name":"Sir Peter Mansfield Image Centre University of Nottingham Nottingham UK"},{"name":"Academic Neurology, Mental Health and Clinical Neuroscience Academic Unit University of Nottingham School of Medicine Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Paine","sequence":"additional","affiliation":[{"name":"School of Medicine University of Nottingham Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases Queen Square Institute of Neurology, University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Ryten","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at The University of Cambridge Cambridge UK"},{"name":"Department of Clinical Neurosciences, School of Clinical Medicine The University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, Queen Square Institute of Neurology University College London London UK"},{"name":"National Institute for Health Research University College London Hospitals Biomedical Research Centre London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"SundalC WszolekZK.CSF1R\u2010Related Adult\u2010Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia [online]. GeneReviews\u00ae;1993. Accessed at:http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22934315."},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1212\/WNL.0000000000006642","article-title":"CSF1R \u2010related leukoencephalopathy","volume":"91","author":"Konno T","year":"2018","journal-title":"Neurology"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/B978-0-323-99209-1.00005-3","article-title":"Adult\u2010onset leukoencephalopathy with axonal spheroids and pigmented glia","volume":"204","author":"Wade C","year":"2024","journal-title":"Handb Clin Neurol"},{"key":"e_1_2_7_5_1","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000200187","article-title":"Global presence and penetrance of CSF1R\u2010related disorder","volume":"10","author":"Dulski J","year":"2024","journal-title":"Neurol Genet"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: clinical interpretation of genetic variants by the 2015 ACMG\u2010AMP guidelines","volume":"100","author":"Li Q","year":"2017","journal-title":"Am J Hum Genet"},{"key":"e_1_2_7_7_1","unstructured":"Association for Clinical Genomic Science.ACGS Best Practice Guidelines for Variant Classification in Rare Disease;2024.https:\/\/www.acgs.uk.com\/quality\/best-practice-guidelines."},{"key":"e_1_2_7_8_1","first-page":"10","article-title":"CSF1R\u2010related disorder","volume":"10","author":"Wade C","year":"2024","journal-title":"Neurol Genet"},{"key":"e_1_2_7_9_1","unstructured":"PanelApp.Adult onset leukodystrophy (Version 6.10) [online];https:\/\/panelapp.genomicsengland.co.uk\/panels\/579\/."},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.64898\/2025.12.30.25342835"},{"key":"e_1_2_7_11_1","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1002\/mds.30282","article-title":"Hematopoietic stem cell transplantation in an international cohort of colony stimulating factor\u20101 receptor (CSF1R)\u2010related disorder","volume":"40","author":"Yska HAF","year":"2025","journal-title":"Mov Disord"}],"container-title":["Movement Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.70366","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mds.70366","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.70366","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T02:12:23Z","timestamp":1779415943000},"score":1,"resource":{"primary":{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/10.1002\/mds.70366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":10,"alternative-id":["10.1002\/mds.70366"],"URL":"https:\/\/doi.org\/10.1002\/mds.70366","archive":["Portico"],"relation":{},"ISSN":["0885-3185","1531-8257"],"issn-type":[{"value":"0885-3185","type":"print"},{"value":"1531-8257","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,21]]},"assertion":[{"value":"2026-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"mds.70366"}}