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Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2 mosaic mutations identified by amplicon deep sequencing
  1. Benjamin Nota1,
  2. Eline M Hamilton2,
  3. Daoud Sie3,
  4. Senay Ozturk1,
  5. Silvy J M van Dooren1,
  6. Matilde R Fernandez Ojeda1,
  7. Cornelis Jakobs1,
  8. Ernst Christensen4,
  9. Edwin P Kirk5,
  10. Jolanta Sykut-Cegielska6,
  11. Allan M Lund4,
  12. Marjo S van der Knaap2,7,
  13. Gajja S Salomons1
  1. 1Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
  3. 3Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
  4. 4Department of Clinical Genetics, Center for Inherited Metabolic Diseases, Copenhagen University Hospital, Copenhagen, Denmark
  5. 5Department of Medical Genetics, Sydney Children's Hospital, Randwick, Australia
  6. 6Department of Metabolic Diseases, Children's Memorial Health Institute, Warsaw, Poland
  7. 7Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
  1. Correspondence to Dr Benjamin Nota, Department of Clinical Chemistry, VU University Medical Center, Metabolic Laboratory, PK 1-X-010, de Boelelaan 1117 Amsterdam 1081 HV, The Netherlands; benjamin.nota{at} or Gajja S Salomons; g.salomons{at}


Background Mosaic IDH1 mutations are described as the cause of metaphyseal chondromatosis with increased urinary excretion of D-2-hydroxyglutarate (MC-HGA), and mutations in IDH2 as the cause of D-2-hydroxyglutaric aciduria (D-2HGA) type II. Mosaicism for IDH2 mutations has not previously been reported as a cause of D-2HGA. Here we describe three cases: one MC-HGA case with IDH1 mosaic mutations, and two D-2HGA type II cases. In one D-2HGA case we identified mosaicism for an IDH2 mutation as the genetic cause of this disorder; the other D-2HGA case was caused by a heterozygous IDH2 mutation, while the unaffected mother was a mosaic carrier.

Methods We performed amplicon deep sequencing using the 454 GS Junior platform, next to Sanger sequencing, to identify and confirm mosaicism of IDH1 or IDH2 mutations in MC-HGA or D-2HGA, respectively.

Results and conclusions We identified different mutant allele percentages in DNA samples derived from different tissues (blood vs fibroblasts). Furthermore, we found that mutant allele percentages of IDH1 decreased after more passages had occurred in fibroblast cell cultures. We describe a method for the detection and validation of mosaic mutations in IDH1 and IDH2, making quantification with laborious cloning techniques obsolete.

  • Inborn Error of Metabolism
  • 2-hydroxyglutarate
  • Mosaicism
  • Neurometabolic Disorder
  • Cancer

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