Four genes associated with isolated dystonia are currently well replicated and validated. DYT-THAP1 manifests as young-onset generalized dystonia with predominant craniocervical symptoms; and is associated with mostly deleterious missense variation in the THAP1 gene. De novo and inherited missense and protein truncating variation in GNAL as well as primarily missense variation in ANO3 cause isolated focal and/or segmental dystonia with preference for the upper half of the body and older ages at onset. The GAG deletion in TOR1A is associated with generalized dystonia with onset in childhood in the lower limbs. Rare variation in these genes causes monogenic sporadic and inherited forms of isolated dystonia; common variation may confer risk and imply that dystonia is a polygenic trait in a subset of cases. Although candidate gene screens have been successful in the past in detecting gene-disease associations, recent application of whole-genome and whole-exome sequencing methods enable unbiased capture of all genetic variation that may explain the phenotype. However, careful variant-level evaluation is necessary in every case, even in genes that have previously been associated with disease. We review the genetic architecture and phenotype of DYT-THAP1, DYT-GNAL, DYT-ANO3, and DYT-TOR1A by collecting case reports from the literature and performing variant classification using pathogenicity criteria.
Keywords: ANO3; Dystonia; Exome sequencing; GNAL; THAP1; TOR1A.