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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls.
Parkinsonism Relat. Disord. 31, 119-123 (2016)
BACKGROUND: An increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts. METHODS: We screened the entire coding sequence and the 5'-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-ΔGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset. RESULTS: In the case cohort, we identified a rare 5'-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-ΔGAG variants was 0.4%. CONCLUSIONS: Our study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Dyt1 ; Dystonia ; Gene ; Rare Variant Analysis ; Tor1a; Mutation; Phenotypes; Genetics
ISSN (print) / ISBN
1353-8020
e-ISSN
1873-5126
Zeitschrift
Parkinsonism & Related Disorders
Quellenangaben
Band: 31,
Seiten: 119-123
Verlag
Elsevier
Verlagsort
Oxford
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed