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

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

Movement Disorders · Published 2025-11-07

Ana Westenberger, Edgard Verdura, Mandy Radefeldt, Leslie E. Sanderson, Kornelia Tripolszki, Anna Marcé‐Grau, Ana Cazurro‐Gutiérrez, Anita Nikoncuk, Rebecca Herzog, Ruslan Al‐Ali, Mariana Ferreira, Ligia S. Almeida, Tainá Regina Damaceno Silveira, Suliman Khan, Raphael Doyle Maia, Péter Klivényi, András Salamon, Volkan Baltaci, Asli Subasioglu, Jeanette Prada‐Arismendy, Goran Čuturilo, Sebastian Loens, Vera Tadic, Isabelle Maystadt, Deniz Karadurmus, Barbara Leube, Jonathan De Winter, Alice Monticelli, Liesbeth De Waele, Jonathan Baets, Mateja Vinkšel, Aleš Maver, Lorena Tschopp, Gabriela Ziegler, Ana Sanguinetti, Katja Lohmann, Tahsin Stefan Barakat, Peter Bauer, Belén Perez‐Dueñas, Aida M. Bertoli‐Avella

Read the original publication

A plain-language reading has not been prepared for this paper yet.

Original abstract

Abstract 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.