Genotype-Phenotype Correlations in THAP1-Associated Dystonia: A Multicentric Observational Study

DYT-THAP1 is a recognized cause of early-onset isolated dystonia. However, available data are largely derived from European cohorts, limiting understanding of genetic diversity, phenotype variability, and treatment response in underrepresented populations.

To characterize the clinical spectrum, genetic architecture, genotype-phenotype correlations, and treatment outcomes in Asian Indian patients with DYT-THAP1.

This multicentric, cross-sectional study included patients harboring pathogenic or likely pathogenic THAP1 variants. Clinical features, neuroimaging, and treatment responses were systematically assessed. Genetic testing comprised whole-exome sequencing, clinical exome sequencing, targeted gene panels, or Sanger sequencing. Variants were classified using ACMG criteria, and genotype-phenotype associations were analyzed.

Twenty-six patients from 22 families were identified (17 males; mean age 29.4 ± 12.9 years). Median age at onset was 13.0 years (IQR 10.0-23.5), with 69.2% presenting before 20 years. Dystonia commonly involved the upper limbs (68%), cervical region (28%), and larynx (20%) at onset, with progression to generalized dystonia in 64%. Seventeen distinct heterozygous THAP1 variants were detected, of which 10 (58.8%) were novel. Loss-of-function variants affected 57.7% of patients and were associated with greater motor severity (P = 0.023) and more frequent positive family history (P = 0.019). Exon 2 variants were more frequent in patients with tremor (P = 0.045).

This study highlights the evolving mutational landscape of DYT-THAP1 beyond variants reported in Caucasian pedigrees and demonstrates novel, clinically relevant genotype-phenotype associations, underscoring the value of including underrepresented populations to bridge knowledge gaps in rare diseases.