title: Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls.
abstract: 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.
  
  
  
  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.
  
  
  
  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%.
  
  
  
  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.
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zech
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Jochim
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Boesch
authors.affiliation: Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Weber
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meindl
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria; Vivantes Klinikum Spandau, Berlin, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Mueller
authors.affiliation: Schön Klinik München Schwabing, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Messner
authors.affiliation: Schön Klinik München Schwabing, Munich, Germany.
authors.forename: Andres
authors.initials: A
authors.lastname: Ceballos-Baumann
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Haslinger
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany. Electronic address: winkelmann@lrz.tu-muenchen.de.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019295:Computational Biology; D004421:Dystonia / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D044465:White People; D055815:Young Adult
chemical_list: D018832:Molecular Chaperones; C108175:TOR1A protein, human
keywords: DYT1; Dystonia; Gene; Rare variant analysis; TOR1A