{
  "abstract": "Introduction Incomplete penetrance and variable expressivity characterize autosomal dominant neurological disorders, but their genetic determinants remain largely unknown. DYT- TOR1A dystonia provides a model for investigating incomplete penetrance. We aimed to identify modifiers of disease penetrance and severity beyond the known TOR1A c.646G>C modifier. Methods In a prospective genotype–phenotype association study, we phenotyped Ashkenazi Jewish carriers of TOR1A c.907_909del using a prespecified five-level severity score. The primary analysis compared participants with no or minimal dystonia (scores 0–1) and severe dystonia (scores 3–4), after excluding c.646G>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. Results The prospective cohort included 61 carriers: 21 had severe dystonia and 28 had no or minimal dystonia, six of whom carried c.646G>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>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>C and local haplotype status predicted the phenotype of more than two-thirds of carriers. In silico analyses linked haplotype B to lower TOR1A and higher TOR1B expression in dystonia-relevant brain regions. Conclusion A common local haplotype in trans to the disease-causing TOR1A variant was strongly associated with reduced penetrance and severity. These findings establish DYT- TOR1A dystonia as a model for investigating how local genetic variation contributes to incomplete penetrance in autosomal dominant neurological disorders.",
  "abstract_shown": true,
  "affiliations": [
    "Hadassah medical center"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "R. Dayan"
    },
    {
      "name": "O. Halstuk"
    },
    {
      "name": "S. Yanovsky-Dagan"
    },
    {
      "name": "J. Rips"
    },
    {
      "name": "C. Rosenbluh"
    },
    {
      "name": "I. Livyatan"
    },
    {
      "name": "M. Grunin"
    },
    {
      "name": "M. Plesser-Duvdevani"
    },
    {
      "name": "H. Bergman"
    },
    {
      "name": "T. Ben Hur"
    },
    {
      "name": "J. R. Lupski"
    },
    {
      "name": "D. Raymond"
    },
    {
      "name": "S. Bressman"
    },
    {
      "name": "R. saunders-pullman"
    },
    {
      "name": "A. Domingo"
    },
    {
      "name": "L. J. Ozelius"
    },
    {
      "name": "S. Carmi"
    },
    {
      "name": "T. Harel"
    },
    {
      "name": "D. Arkadir"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4v4ratf41v7tx.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.05.26361794",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.05.26361794v1.full",
  "id": "4v4ratf41v7tx",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.05.26361794v1",
  "language": null,
  "licence": "PDM-1.0",
  "licence_label": "Public domain",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/publicdomain/mark/1.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ],
    [
      "openalex",
      "2728|Neurological disorders and treatments"
    ]
  ],
  "openalex": "W7212175233",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.05.26361794v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4v4ratf41v7tx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:18Z",
      "native_id": "10.64898/2026.09.05.26361794",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.05.26361794v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "A Protective Haplotype in trans Modifies Penetrance and Severity of TOR1A Dystonia",
  "title_text": "A Protective Haplotype in trans Modifies Penetrance and Severity of TOR1A Dystonia",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:18Z",
  "url": "https://research.draconitic.com/paper/4v4ratf41v7tx",
  "venue": "medRxiv",
  "versions": []
}