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However, in a fraction of patients,\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      coding variants are not detected, and variants outside the\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      locus have been reported.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The objective of this study was to evaluate the clinical spectrum and frequency of regulatory variants in\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      \u2010RDs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Eight families carrying structural variants near\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      without disruption of the coding sequence were recruited, and clinical data were systematically collected. Regulatory activity was assessed using EpiMap data. Frequency and diagnostic yield were evaluated in a cohort of 26 individuals with molecularly confirmed\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      \u2010RD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Eight families comprising 13 affected individuals were identified: five with downstream deletions and three with complex structural rearrangements. Neurological manifestations were universal, including chorea, myoclonus, and ataxia, while cognitive or behavioral abnormalities occurred in a subset. Individuals with deletions rarely presented extraneurological features, whereas all carriers of complex structural variants showed the complete triad. All deletions and breakpoints were located downstream of\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      . The core shared deleted region showed open chromatin and H3K27ac peaks in fetal brain, lung, and thyroid tissues, suggesting regulatory activity. Regulatory variants accounted for 27% of\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      \u2010RD diagnoses in our institutions. Exome sequencing combined with copy\u2010number variant analysis captured 92% of diagnoses when\n                      <jats:italic>MBIP<\/jats:italic>\n                      was evaluated as a target for downstream variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Downstream regulatory variants are a substantial cause of\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      \u2010RDs. Diagnostic strategies should include this regulatory region and systematic structural variant detection, particularly when coding variants have been excluded. \u00a9 2026 The Author(s).\n                      <jats:italic>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.70432","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:54:26Z","timestamp":1784267666000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>\n                      <scp>NKX2<\/scp>\n                      \u20101\n                    <\/i>\n                    Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0138-5833","authenticated-orcid":false,"given":"Robin","family":"Wijngaard","sequence":"first","affiliation":[{"name":"Department of Human Genetics Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center  Nijmegen Netherlands"},{"name":"United for Metabolic Diseases (UMD)  Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8865-2438","authenticated-orcid":false,"given":"Lucy","family":"Dougherty\u2010de Miguel","sequence":"additional","affiliation":[{"name":"Therapeutics and Innovations in Neuropediatrics and other paediatric rare diseases, Vall d'Hebron Institute of Research (VHIR) Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d'Hebron (IIS IR\u2010HUVH)  Barcelona Spain"},{"name":"Department of Pediatric Neurology University Hospital Vall d'Hebron (HUVH), Vall d'Hebron University Hospital Research Institute (IIS IR\u2010HUVH)  Barcelona Spain"},{"name":"Department of Pediatrics Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9075-4276","authenticated-orcid":false,"given":"German","family":"Demidov","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1524-0619","authenticated-orcid":false,"given":"Galuh","family":"Astuti","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9136-5106","authenticated-orcid":false,"given":"Amaia","family":"Lasa\u2010Aranzasti","sequence":"additional","affiliation":[{"name":"Clinical 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