A Protective Haplotype in trans Modifies Penetrance and Severity of TOR1A Dystonia
- 1Hadassah medical center
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.
Related
- The APOL1 protective M1 modifier occurs exclusively with the KIK protein haplotype to suppress channel conductance
- Pallidal Local Field Potentials markers of dystonia aetiology and severity in children
- Perceived severity and benefits show a preliminary conditional association with kidney-protective behaviors in type 2 diabetes with early kidney function decline: an exploratory health belief model analysis
- Ubiquitin Proteasome System BTB-Adaptor Protein Insomniac Modifies Seizure Severity and Response to the Ketogenic Diet in a Drosophila Model of Mitochondrial Encephalomyopathy.
- Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model
BibTeX
@misc{dayan2026protective,
title = {{A Protective Haplotype in trans Modifies Penetrance and Severity of TOR1A Dystonia}},
author = {R. Dayan and O. Halstuk and S. Yanovsky-Dagan and J. Rips and C. Rosenbluh and I. Livyatan and M. Grunin and M. Plesser-Duvdevani and H. Bergman and T. Ben Hur and J. R. Lupski and D. Raymond and S. Bressman and R. saunders-pullman and A. Domingo and L. J. Ozelius and S. Carmi and T. Harel and D. Arkadir},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.05.26361794},
url = {https://www.medrxiv.org/content/10.64898/2026.09.05.26361794v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - A Protective Haplotype in trans Modifies Penetrance and Severity of TOR1A Dystonia
AU - R. Dayan
AU - O. Halstuk
AU - S. Yanovsky-Dagan
AU - J. Rips
AU - C. Rosenbluh
AU - I. Livyatan
AU - M. Grunin
AU - M. Plesser-Duvdevani
AU - H. Bergman
AU - T. Ben Hur
AU - J. R. Lupski
AU - D. Raymond
AU - S. Bressman
AU - R. saunders-pullman
AU - A. Domingo
AU - L. J. Ozelius
AU - S. Carmi
AU - T. Harel
AU - D. Arkadir
PY - 2026
DA - 2026/09/05
PB - medRxiv
DO - 10.64898/2026.09.05.26361794
UR - https://www.medrxiv.org/content/10.64898/2026.09.05.26361794v1
AB - 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.
ER -