DRD1 rare variants associated with tardive-like dystonia: a pilot pathway sequencing study in dystonia.
The dystonias are a clinical heterogeneous group with a complex genetic background. To gain more insight in genetic risk factors in dystonia we used a pathway sequence approach in patients with an extreme dystonia phenotype (n = 26). We assessed all coding and non-coding variants in candidate genes in D1-like subclass of dopamine receptor genes (DRD1, DRD5) and the synaptic vesicle pathway linked to torsinA (TOR1A, STON2, SNAPIN, KLC1 and THAP1), spanning 96 Kb. Two rare missense variants in DRD1 were found: c.68G>A(p.Arg23His) in the screening group and c.776C>A(p.Ser259Tyr) in an additional screen of 15 selected dystonia patients. Genetic burden analysis of DRD1 rare variants in patients (4.8%) versus European American controls from ESP (0.72%) reveals an OR 5.35 (95% CI 1.29-23.1). No rare missense SNVs in the synaptic vesicle pathway were found. Sequencing of TOR1A showed variant enrichment in haplotype 2, possibly accountable for contradictive results in previous association studies. Two new rare SNVs were detected in THAP1, including a nonsense mutation (p.Gln167Ter) and a splice site variant (c.72-1G>A). Screening for rare SNV of candidate pathways in a phenotype extreme population appears to be a promising alternative method to identify genetic risk factors in complex disorders like primary torsion dystonia. These findings indicate a role for rare genetic variation in dopamine processing genes in dystonia pathophysiology.
Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Justus L
JL
Groen
Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Katja
K
Ritz
Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.
Tom T
TT
Warner
Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Frank
F
Baas
Department of Neurology, University of Groningen, The Netherlands. Electronic address: M.A.J.de.Koning-Tijssen@umcg.nl.
Marina A J
MA
Tijssen
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D020821:Dystonic Disorders / Q000175:diagnosis / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D016547:Kinesins; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders / Q000175:diagnosis* / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010865:Pilot Projects; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D055815:Young Adult
C583260:DRD1 protein, human; C000715688:KLC1 protein, human; D017447:Receptors, Dopamine D1; D016547:Kinesins
DRD1; Dystonia; Pathway sequencing