title: Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy.
abstract: BACKGROUND
  Biotin-thiamine responsive basal ganglia disease is a severe, but potentially treatable disorder caused by mutations in the SLC19A3 gene. Although the disease is inherited in an autosomal recessive manner, patients with typical phenotypes carrying single heterozygous mutations have been reported. This makes the diagnosis uncertain and may delay treatment.
  
  
  RESULTS
  In two siblings with early-onset encephalopathy dystonia and epilepsy, whole-exome sequencing revealed a novel single heterozygous SLC19A3 mutation (c.337T>C). Although Sanger-sequencing and copy-number analysis revealed no other aberrations, RNA-sequencing in brain tissue suggested the second allele was silenced. Whole-genome sequencing resolved the genetic defect by revealing a novel 45,049 bp deletion in the 5'-UTR region of the gene abolishing the promoter. High dose thiamine and biotin therapy was started in the surviving sibling who remains stable. In another patient two novel compound heterozygous SLC19A3 mutations were found. He improved substantially on thiamine and biotin therapy.
  
  
  CONCLUSIONS
  We show that large genomic deletions occur in the regulatory region of SLC19A3 and should be considered in genetic testing. Moreover, our study highlights the power of whole-genome sequencing as a diagnostic tool for rare genetic disorders across a wide spectrum of mutations including non-coding large genomic rearrangements.
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Irene
authors: I
authors: Flønes
authors: Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.|Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
authors: Paweł
authors: P
authors: Sztromwasser
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Kristoffer
authors: K
authors: Haugarvoll
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Christian
authors: C
authors: Dölle
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Maria
authors: M
authors: Lykouri
authors: Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Radiology, Haukeland University Hospital, Bergen, Norway.
authors: Thomas
authors: T
authors: Schwarzlmüller
authors: Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
authors: Inge
authors: I
authors: Jonassen
authors: Department of Pathology, Haukeland University Hospital, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.|KG Jebsen Brain Tumor Research Center, University of Bergen, Bergen, Norway.
authors: Hrvoje
authors: H
authors: Miletic
authors: Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.|K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors: Stefan
authors: S
authors: Johansson
authors: Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.|K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors: Per M
authors: PM
authors: Knappskog
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Laurence A
authors: LA
authors: Bindoff
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Charalampos
authors: C
authors: Tzoulis
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000483:Alleles; D001479:Basal Ganglia / Q000378:metabolism*; D001480:Basal Ganglia Diseases / Q000235:genetics*; D001710:Biotin / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D035781:Siblings; D013831:Thiamine / Q000378:metabolism; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; D026901:Membrane Transport Proteins; C492291:SLC19A3 protein, human; D001710:Biotin; D013831:Thiamine