Category: Dystonia: Genetics
Objective: To systematically investigate the occurrence of pathogenic variants in genes linked to neurodevelopmental disorders (NDD) in patients with dystonia.
Background: Partially overlapping genetic causes have been suggested for dystonia and NDD based on clinical, genetic, and neurobiological features, suggesting that pathogenic variants in some additional NDD genes could also contribute to the development of dystonia.
Method: We included 1,924 patients with dystonia, recruited via the DysTract and DystoniaCoalition registries and from a Movement Disorder Center in Kuala Lumpur, Malaysia. Most patients (>90%) had reportedly isolated dystonia and >50% had focal dystonia only, with cervical dystonia being the most common subtype. Exome sequencing was conducted on these patients. A total of 1,374 DDG2P-listed genes linked to NDD were selected and screened for potentially pathogenic variants in patients with dystonia. We looked for variants consistent with the reported mode of inheritance (Tier 1) and for single heterozygous variants in recessive NDD genes (Tier 2). Reverse phenotyping was performed when possible.
Results: In Tier 1, we identified 179 pathogenic/likely pathogenic variants in 108 NDD genes in 170 patients (8.8%). Most of these patients had a pure dystonia phenotype, while 13 patients showed clinical features at least partially consistent with known phenotype-genotype relationships. Tier 2 analysis revealed 313 single heterozygous pathogenic/likely pathogenic variants in 211 recessive NDD genes. Four pathogenic heterozygous variants were recurrently found in the autosomal dominant NDD gene POLR3B, as well as in the autosomal recessive NDD genes AP4E1, ATR, and GALNS.
Conclusion: This study revealed pathogenic/likely pathogenic variants in NDD genes in almost 10% of patients with dystonia and underlines the shared genetic basis of dystonia and NDD. Follow-up studies across different cohorts are warranted to confirm a subset of these NDD genes as dystonia genes. Notably, our data support the hypothesis that some subtypes of dystonia are neurodevelopmental disorders, at least in a proportion of patients.
To cite this abstract in AMA style:
L. Welzel, M. Thomsen, G. Kilic-Berkmen, S. Loens, E. Lohmann, AH. Tan, S. Frank, A. Lang, J. Perlmutter, M. Möller, S. Franzenburg, SY. Lim, A. Münchau, HA. Jinnah, H. Busch, T. Bäumer, D., D., C. Klein, K. Lohmann. High Frequency of Pathogenic Variants in Neurodevelopmental Genes in Patients with Dystonia [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/high-frequency-of-pathogenic-variants-in-neurodevelopmental-genes-in-patients-with-dystonia/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/high-frequency-of-pathogenic-variants-in-neurodevelopmental-genes-in-patients-with-dystonia/