A Protective Haplotype in trans Modifies Penetrance and Severity of TOR1A Dystonia

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.