Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy

PLoS One. 2016 Feb 10;11(2):e0149055. doi: 10.1371/journal.pone.0149055. eCollection 2016.

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.

Methods and 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Adolescent
  • Alleles
  • Basal Ganglia / metabolism*
  • Basal Ganglia Diseases / genetics*
  • Biotin / metabolism
  • Brain / metabolism
  • Exome
  • Fatal Outcome
  • Female
  • Gene Deletion
  • Gene Silencing*
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Male
  • Membrane Transport Proteins / genetics*
  • Mutation
  • Phenotype
  • Promoter Regions, Genetic*
  • Sequence Analysis, DNA
  • Siblings
  • Thiamine / metabolism
  • Young Adult

Substances

  • 5' Untranslated Regions
  • Membrane Transport Proteins
  • SLC19A3 protein, human
  • Biotin
  • Thiamine

Supplementary concepts

  • Basal ganglia disease, biotin-responsive

Grant support

This work was supported (authors CT and PMK) by grants from the Regional Health Authority of Western Norway (Helse Vest, http://www.helse-vest.no/en/Sider/default.aspx, grant no 911903 and 911810), and the Bergen Research Foundation bioinformatics grant. These grants covered the expenses for the genetic tests and analyses.