Expanding the Genetic and Phenotypic Spectrum of DYT-VPS16: The Importance of Splice-Site Variants.

BACKGROUND

DYT-VPS16, an early-onset isolated dystonia caused by variants in the VPS16 gene, has been reported in fewer than 70 patients.

METHODS

We explored the clinical and genotypic spectrum of DYT-VPS16 by investigating early-onset dystonia patients with VPS16 variants discovered in our large Biodatabank and through gene-matching initiatives. Patient samples were analyzed by exome/Sanger and RNA/cDNA sequencing.

RESULTS

We identified 16 previously unreported DYT-VPS16 patients (7 male, median age at onset [AAO]: 12 years). Patients with initial leg involvement had an AAO more than 10 years earlier than those with involvement of the arms/craniocervical region. Dystonia progressed in 95%, generalized in 50%, and was accompanied by pyramidal, cerebellar, or psychiatric features in 25% of patients. Two young individuals benefited greatly from timely deep brain stimulation (DBS) surgery. Of the 11 identified VPS16 variants, 10 were novel. Utilizing RNA-Seq or cDNA sequencing, we discovered alternatively spliced transcripts, thereby elucidating the effects of splice-site, near-splice-site, and exonic variants.

CONCLUSIONS

We expand the phenotypic and mutational spectrum of DYT-VPS16, emphasize the utility of RNA-Seq in clarifying VPS16 variant pathogenicity, and advocate for timely DBS as a promising therapeutic option for DYT-VPS16 patients. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.