Objective: To describe a case of dystonia DYT6 in which a variant of uncertain significance (VUS) in the THAP1 gene was found, which is likely pathogenic

Background: We present a 58-year-old man who presented dysphagia and dysarthria at the age of 22. These symptoms progressed mildly, and 10 years later, he developed difficulty mobilizing his upper limbs with dystonic posturing, initially affecting the upper limbs. Over time, this progressed to involve face and neck. The patient’s father had a very similar condition. A dystonia panel was performed, revealing the presence in heterozygosity of a variant described as NM_018105.3 (thap1): c.108G>T;p (Trp36Cys) in the THAP1 gene, a variant classified as VUS

Method: We conducted a literature review to investigate if there is a description of this variant associated with DYT6, as well as to gather clinical descriptions of the disease

Results: Dystonia is a disorder characterized by uncontrollable involuntary movements along with abnormal postures. DYT6 is an autosomal dominant genetic disease with incomplete penetrance and a highly variable age of onset. It can present with different phenotypes and tends to progress slowly, initially presenting in about 50% of cases in the upper limbs or cranio-cervical region. Currently, the main treatments are the use of botulinum toxin and deep brain stimulation. Variations in the THAP1 gene have been associated with DYT6, although the specific mechanism by which these alterations cause the disease is not currently clear. In 2011, the UMD-THAP1 database was created, describing 53 mutations at that time, with around 65% being missense mutations. Currently, 89 different variants are described. The genetic database ClinVar describes 33 variants considered pathogenic for this gene. The variant describes a nucleotide change at position 108 of the cDNA results in an amino acid change at position 36, which has not been described until now, with only one description cataloged as pathogenic at this position of complementary DNA. We used the Franklin ACMG classification tool to describe this variant, classifying it as likely pathogenic

Conclusion: DYT6 is an autosomal dominant disease that presents with slowly progressive symptoms and can be focal, segmental, or generalized. Various variations in the THAP1 gene are associated with this disease, with the variant found in this patient being described as likely pathogenic

References: 1. Koptielow J, Szyłak E, Szewczyk-Roszczenko O, Roszczenko P, Kochanowicz J, Kułakowska A, Chorąży M. Genetic Update and Treatment for Dystonia. Int J Mol Sci. 2024 Mar 22;25(7):3571. doi: 10.3390/ijms25073571.
2. Klein C, Lohmann K, Marras C, et al. Hereditary Dystonia Overview. 2003 Oct 28 [Updated 2017 Jun 22]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1155/
3. Blanchard A, Ea V, Roubertie A, Martin M, Coquart C, Claustres M, Béroud C, Collod-Béroud G. DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. Hum Mutat. 2011 Nov;32(11):1213-24. doi: 10.1002/humu.21564.
4. Zakin E., Simpson D.M. Botulinum Toxin Therapy in Writer’s Cramp and Musician’s Dystonia. Toxins. 2021;13:899. doi: 10.3390/toxins13120899.
5. Duarte G.S., Rodrigues F.B., Marques R.E., Castelão M., Ferreira J., Sampaio C., Moore A.P., Costa J. Botulinum Toxin Type A Therapy for Blepharospasm. Cochrane Database Syst. Rev. 2020;2020:CD004900. doi: 10.1002/14651858.CD004900.pub3.
6. Ramirez-Castaneda J., Jankovic J. Long-Term Efficacy, Safety, and Side Effect Profile of Botulinum Toxin in Dystonia: A 20-Year Follow-Up. Toxicon. 2014;90:344–348. doi: 10.1016/j.toxicon.2014.07.009
7. Albanese A., Asmus F., Bhatia K.P., Elia A.E., Elibol B., Filippini G., Gasser T., Krauss J.K., Nardocci N., Newton A., et al. EFNS Guidelines on Diagnosis and Treatment of Primary Dystonias. Eur. J. Neurol. 2011;18:5–18. doi: 10.1111/j.1468-1331.2010.03042.x.
8. Fan H., Zheng Z., Yin Z., Zhang J., Lu G. Deep Brain Stimulation Treating Dystonia: A Systematic Review of Targets, Body Distributions and Etiology Classifications. Front. Hum. Neurosci. 2021;15:757579. doi: 10.3389/fnhum.2021.757579.
9. Danielsson A, Carecchio M, Cif L, Koy A, Lin JP, Solders G, Romito L, Lohmann K, Garavaglia B, Reale C, Zorzi G, Nardocci N, Coubes P, Gonzalez V, Roubertie A, Collod-Beroud G, Lind G, Tedroff K. Pallidal Deep Brain Stimulation in DYT6 Dystonia: Clinical Outcome and Predictive Factors for Motor Improvement. J Clin Med. 2019 Dec 6;8(12):2163. doi: 10.3390/jcm8122163.
10. Zakirova Z, Fanutza T, Bonet J, Readhead B, Zhang W, Yi Z, Beauvais G, Zwaka TP, Ozelius LJ, Blitzer RD, Gonzalez-Alegre P, Ehrlich ME. Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. PLoS Genet. 2018 Jan 24;14(1):e1007169. doi: 10.1371/journal.pgen.1007169.
11. ClinVar Miner. List of variants in gene THAP1 reported as pathogenic for generalized dystonia [Internet]. Utah: University of Utah; [cited 2025 Mar 14]. Available from: https://clinvarminer.genetics.utah.edu/variants-by-mondo-condition/476/gene/THAP1/pathogenic
12. Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, Saunders-Pullman R. Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol. 2009 May;8(5):441-6. doi: 10.1016/S1474-4422(09)70081-X.
13. Genoox. Franklin ACMG Classification. [Internet]. United States of America; [cited 2024 Dec 10]. Available from: https://franklin.genoox.com/clinical-db/home

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/undescribed-variant-of-the-thap1-gene-likely-pathogenic-associated-with-dyt6-case-report/