Objective: We have identified a novel heterozygous missense mutation in THAP1 (DYT6 locus) in a patient suffering from craniocervical and upper limb dystonia. We describe the clinical features of the index patient and her daughter, who both presented dystonic symptoms.

Background: The spectrum of etiological factors predisposing to dystonia is broad and currently not completely elucidated. Several causal genes for monogenic dystonia syndromes have been identified. Mutations in TOR1A, THAP1 and GNAL have been identified in monogenic forms of isolated dystonia (i.e. dystonic syndrome with absence of other associated movement disorders). Patients carrying mutations in THAP1 can present with focal, segmental or generalized dystonia, with predilection for craniocervical involvement.

Methods: Sanger sequencing of all coding exons and intron-exon boundaries of THAP1 was performed in the index patient and her daughter. The c.907_909delGAG deletion in TOR1A was excluded in the index patient.

Results: The 55-year old female index patient suffered from late-onset cervical dystonia with dystonic head tremor and later developed upper limb dystonia. The onset of the dystonic symptoms was in the 5th decade. Her daughter presented a very mild craniocervical dystonia, which became apparent in young adulthood. The dystonic symptoms responded well to botulinum toxin injections in both patients. Sanger sequencing of THAP1 revealed a novel heterozygous missense variant in exon 1 leading to an amino acid substitution in a DNA binding domain of the protein. In silico analysis to assess the putative pathogenic effect of this missense variant was inconclusive, however the variant was neither reported in the 1000 Genomes Project nor in the Exome Sequencing Project.

Conclusions: We report a novel heterozygous missense mutation in exon 1 of THAP1 (DYT6 locus). The associated phenotype in the index patient and her daughter consists of focal and segmental dystonia with clear predominance of craniocervical symptoms. The pathogenicity of this novel missense variant is supported by co-segregation with the dystonia phenotype, by absence of the variant in publicly available whole genome/exome databases and finally by a previous report of a pathogenic amino acid substitution at the same position of the THAP1 protein in a familial dystonia patient. We have broadened the mutational spectrum of THAP1 and our findings confirm the phenotypic heterogeneity of DYT-THAP1.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-thap1-missense-mutation-leading-to-focal-and-segmental-dystonia/