{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:08:04Z","timestamp":1789211284968,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,10]]},"group-title":"Neurology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/006wb1h58","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Israeli Center for Addictions and Mental Health"},{"name":"Berel and Agnes Ginges Family Foundation"},{"name":"United States National Institutes of Health","award":["UO1 HG001798"],"award-info":[{"award-number":["UO1 HG001798"]}]},{"name":"United States National Institutes of Health","award":["R35 NS105078"],"award-info":[{"award-number":["R35 NS105078"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>\n                    Incomplete penetrance and variable expressivity characterize autosomal dominant neurological disorders, but their genetic determinants remain largely unknown. DYT-\n                    <jats:italic>TOR1A<\/jats:italic>\n                    dystonia provides a model for investigating incomplete penetrance. We aimed to identify modifiers of disease penetrance and severity beyond the known\n                    <jats:italic>TOR1A<\/jats:italic>\n                    c.646G&gt;C modifier.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    In a prospective genotype\u2013phenotype association study, we phenotyped Ashkenazi Jewish carriers of\n                    <jats:italic>TOR1A<\/jats:italic>\n                    c.907_909del using a prespecified five-level severity score. The primary analysis compared participants with no or minimal dystonia (scores 0\u20131) and severe dystonia (scores 3\u20134), after excluding c.646G&gt;C carriers. Findings were assessed in an independent retrospective cohort. Sanger, exome, and short-read and long-read whole-genome sequencing were used for genotyping.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The prospective cohort included 61 carriers: 21 had severe dystonia and 28 had no or minimal dystonia, six of whom carried c.646G&gt;C. Among the 43 participants in the primary analysis, haplotype A was identified in 33 (77%) and haplotype B in eight (19%). All haplotype B carriers had no or minimal dystonia (p=0.003). Haplotype B remained associated with a milder phenotype after including 12 participants with intermediate severity (p=0.006). The retrospective cohort included 147 carriers, 16 of whom carried c.646G&gt;C. After their exclusion, dystonia manifested in 12 (38%) of 32 participants with haplotype B and 63 (64%) of 99 without it (p=0.009). Haplotype B was also associated with lower severity scores (p=0.011). Together, c.646G&gt;C and local haplotype status predicted the phenotype of more than two-thirds of carriers. In silico analyses linked haplotype B to lower\n                    <jats:italic>TOR1A<\/jats:italic>\n                    and higher\n                    <jats:italic>TOR1B<\/jats:italic>\n                    expression in dystonia-relevant brain regions.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    A common local haplotype\n                    <jats:italic>in trans<\/jats:italic>\n                    to the disease-causing\n                    <jats:italic>TOR1A<\/jats:italic>\n                    variant was strongly associated with reduced penetrance and severity. These findings establish DYT-\n                    <jats:italic>TOR1A<\/jats:italic>\n                    dystonia as a model for investigating how local genetic variation contributes to incomplete penetrance in autosomal dominant neurological disorders.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.05.26361794","type":"posted-content","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T01:05:12Z","timestamp":1789088712000},"source":"Crossref","is-referenced-by-count":0,"title":["A Protective Haplotype\n                  <i>in trans<\/i>\n                  Modifies Penetrance and Severity of\n                  <i>TOR1A<\/i>\n                  Dystonia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3061-3740","authenticated-orcid":false,"given":"Roy","family":"Dayan","sequence":"first","affiliation":[{"name":"Department of Neurology, Hadassah Medical Center, Jerusalem, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6988-790X","authenticated-orcid":false,"given":"Orli","family":"Halstuk","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"},{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7853-0405","authenticated-orcid":false,"given":"Shira","family":"Yanovsky-Dagan","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9237-8929","authenticated-orcid":false,"given":"Jonathan","family":"Rips","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"},{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3329-1396","authenticated-orcid":false,"given":"Chaggai","family":"Rosenbluh","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5670-7203","authenticated-orcid":false,"given":"Ilana","family":"Livyatan","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3155-2858","authenticated-orcid":false,"given":"Michelle","family":"Grunin","sequence":"additional","affiliation":[{"name":"Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"},{"name":"Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morasha","family":"Plesser-Duvdevani","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2402-6673","authenticated-orcid":false,"given":"Hagai","family":"Bergman","sequence":"additional","affiliation":[{"name":"Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3463-2922","authenticated-orcid":false,"given":"Tamir","family":"Ben Hur","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hadassah Medical Center, Jerusalem, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9907-9246","authenticated-orcid":false,"given":"James R","family":"Lupski","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1403-7739","authenticated-orcid":false,"given":"Deborah","family":"Raymond","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3513-8048","authenticated-orcid":false,"given":"Susan","family":"Bressman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8132-8806","authenticated-orcid":false,"given":"Rachel","family":"Saunders-Pullman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1396-3303","authenticated-orcid":false,"given":"Aloysius","family":"Domingo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7820-1684","authenticated-orcid":false,"given":"Laurie J","family":"Ozelius","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0188-2610","authenticated-orcid":false,"given":"Shai","family":"Carmi","sequence":"additional","affiliation":[{"name":"Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3595-7075","authenticated-orcid":false,"given":"Tamar","family":"Harel","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"},{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1831-5310","authenticated-orcid":false,"given":"David","family":"Arkadir","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hadassah Medical Center, Jerusalem, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091203450876000_2026.09.05.26361794v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70257-6"},{"key":"2026091203450876000_2026.09.05.26361794v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.920390"},{"key":"2026091203450876000_2026.09.05.26361794v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1331-2"},{"key":"2026091203450876000_2026.09.05.26361794v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1578"},{"key":"2026091203450876000_2026.09.05.26361794v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17374-3"},{"key":"2026091203450876000_2026.09.05.26361794v1.6","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232214205"},{"key":"2026091203450876000_2026.09.05.26361794v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20496-3"},{"key":"2026091203450876000_2026.09.05.26361794v1.8","doi-asserted-by":"publisher","DOI":"10.1086\/518427"},{"key":"2026091203450876000_2026.09.05.26361794v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0611-3"},{"key":"2026091203450876000_2026.09.05.26361794v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23491-4"},{"key":"2026091203450876000_2026.09.05.26361794v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0192-y"},{"key":"2026091203450876000_2026.09.05.26361794v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/mds.30141"},{"key":"2026091203450876000_2026.09.05.26361794v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.39"},{"key":"2026091203450876000_2026.09.05.26361794v1.14","doi-asserted-by":"publisher","DOI":"10.3390\/genes11030239"},{"key":"2026091203450876000_2026.09.05.26361794v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09613-8"},{"key":"2026091203450876000_2026.09.05.26361794v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02364-1"},{"key":"2026091203450876000_2026.09.05.26361794v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28485"},{"key":"2026091203450876000_2026.09.05.26361794v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/ng0997-40"},{"key":"2026091203450876000_2026.09.05.26361794v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5835"},{"key":"2026091203450876000_2026.09.05.26361794v1.20","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.54.9.1746"},{"key":"2026091203450876000_2026.09.05.26361794v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06045-0"},{"key":"2026091203450876000_2026.09.05.26361794v1.22","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410360514"},{"key":"2026091203450876000_2026.09.05.26361794v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2012.09.005"},{"key":"2026091203450876000_2026.09.05.26361794v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/mds.23535"},{"key":"2026091203450876000_2026.09.05.26361794v1.25","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.35.1.73"},{"key":"2026091203450876000_2026.09.05.26361794v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2026091203450876000_2026.09.05.26361794v1.27","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhw363"},{"issue":"3","key":"2026091203450876000_2026.09.05.26361794v1.28","first-page":"533","article-title":"Segregation analysis of idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance","volume":"46","year":"1990","journal-title":"Am J Hum Genet"},{"key":"2026091203450876000_2026.09.05.26361794v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv402"},{"key":"2026091203450876000_2026.09.05.26361794v1.30","unstructured":"Ancient Genome Browser. https:\/\/bioinf.eva.mpg.de\/jbrowse"},{"key":"2026091203450876000_2026.09.05.26361794v1.31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000586"},{"key":"2026091203450876000_2026.09.05.26361794v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"2026091203450876000_2026.09.05.26361794v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-10014-0"},{"key":"2026091203450876000_2026.09.05.26361794v1.34","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8"},{"key":"2026091203450876000_2026.09.05.26361794v1.35","doi-asserted-by":"publisher","DOI":"10.1002\/mds.70073"},{"key":"2026091203450876000_2026.09.05.26361794v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/ng0295-152"},{"key":"2026091203450876000_2026.09.05.26361794v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.06.004"},{"key":"2026091203450876000_2026.09.05.26361794v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.12.029"},{"key":"2026091203450876000_2026.09.05.26361794v1.39","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.54285"},{"key":"2026091203450876000_2026.09.05.26361794v1.40","doi-asserted-by":"publisher","DOI":"10.1097\/00125817-200201000-00004"},{"key":"2026091203450876000_2026.09.05.26361794v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2025.06.011"},{"key":"2026091203450876000_2026.09.05.26361794v1.42","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1406829"},{"key":"2026091203450876000_2026.09.05.26361794v1.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010129"},{"key":"2026091203450876000_2026.09.05.26361794v1.44","doi-asserted-by":"publisher","DOI":"10.1097\/01.gim.0000245632.06064.f1"},{"key":"2026091203450876000_2026.09.05.26361794v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(24)00083-8"},{"key":"2026091203450876000_2026.09.05.26361794v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.12.087"},{"key":"2026091203450876000_2026.09.05.26361794v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2025.102759"},{"key":"2026091203450876000_2026.09.05.26361794v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2025.102466"},{"key":"2026091203450876000_2026.09.05.26361794v1.49","doi-asserted-by":"publisher","DOI":"10.1086\/303021"},{"key":"2026091203450876000_2026.09.05.26361794v1.50","doi-asserted-by":"publisher","DOI":"10.1002\/mds.70087"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.05.26361794","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:45:19Z","timestamp":1789209919000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.05.26361794"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":50,"URL":"https:\/\/doi.org\/10.64898\/2026.09.05.26361794","relation":{},"subject":[],"published":{"date-parts":[[2026,9,10]]},"subtype":"preprint"}}