Objective: To present a new case with generalized dystonia carrying a novel heterozygous likely pathogenic THAP1 variant associated with reduced penetrance

Background: Dystonia is a neurological condition characterized by abnormal involuntary movements or postures owing to sustained or intermittent muscle contractions. THAP1 is an established gene associated with generalized dystonia and several mutations have been described. THAP1 mutations are often associated with low penetrance, which complicates establishing pathogenicity of novel missense variants

Method: A 25-year-old female patient presented at age 14 with cervical dystonia that over the years spread to involve the trunk, upper and lower limb, and the oromandibular segment with consequent dysarthria. She had no family history of any movement disorder. An extensive panel for dystonia was requested to investigate the possibility of a genetically determined disease. The patient was considered eligible for DBS and bilateral GPi electrode implantation is currently under discussion

Results: We identified a previously unreported variant in THAP1 (NM_018105.2; exon 2 c.109 G>A; p.Glu37Lys), which was inherited from her unaffected father. The variant has not been previously reported as pathogenic or benign. However, a CADD score of 20 puts it amongst the top 1% most deleterious variants in the human genome. It is present in only 1/125682 subjects reported in gnomAD. Moreover, it is located in the DNA binding domain of the protein, where the majority of pathogenic variants identified up to date are found. According to ACMG/AMP guidelines, our mutation is classified as likely pathogenic

Conclusion: We report a novel missense mutation in THAP1 in a case with a phenotype highly consistent with that of THAP1-related dystonia, including prominent cranio-cervical involvement. This element, together with in silico predictions of deleteriousness and its extreme rarity in the general population, supports its pathogenic role. This result highlights the fact that distinguishing low-penetrant pathogenic variants from rare benign ones is a complex task, even when they are found in established disease-associated genes. Functional assays are strongly warranted to shed light on the effect of THAP1 variants on protein activity. Finally, it’s still under debate to what extent a positive genetic result can influence candidacy for DBS surgery

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-case-of-generalized-early-onset-dystonia-with-a-novel-low-penetrant-thap1-missense-variant/