An activating germline IDH1 variant associated with a tumor entity characterized by unilateral and bilateral chondrosarcoma of the mastoid

Patrick R. Blackburn, Jodi M. Carter, Devin Oglesbee, Jennifer J. Westendorf, Brian A. Neff, Damian Stichel, David W. Tsen, Ralitza H. Gavrilova, Pieter Wesseling, Andreas von Deimling, Thomas R. Caulfield, Eric W. Klee, Stefan Pusch, Carrie Y. Inwards

Research output: Contribution to journalArticlepeer-review


Chondrogenic tumors involving the temporal bone are rare and typically arise spontaneously with unilateral presentation. Somatic IDH mutations are common in these tumors, but germline inheritance has not been documented to our knowledge. We describe familial chondrosarcoma, grade 1, of the mastoid with unilateral presentation in the mother and bilateral presentation in each of her two children. Each individual presented with headaches, facial paresis, and conductive hearing loss between the ages of 9–12. Exome sequencing of all three affected family members identified a shared germline heterozygous c.299G>A (p.Arg100Gln) missense variant in IDH1. The p.Arg100Gln variant has only rarely been observed as a somatic mutation in glial tumors, and previous in vitro experiments have shown that p.Arg100Gln produces small amounts of the oncometabolite D-2-hydroxyglutarate (D2HG). Biochemical testing in all three affected family members on urine and plasma was unable to detect increases in D2HG in these sample types. Due to insufficient tumor for methylation studies, we performed genome-wide methylation analysis of an IDH1 p.Arg100Gln mutant brain tumor from an unrelated individual to functionally evaluate this variant. These studies demonstrated a global hypermethylation phenotype consistent with other known isocitrate dehydrogenase (IDH) mutant brain tumors, suggesting that this variant has neomorphic activity despite low-level production of D2HG. The bones of the facial skeleton are formed by membranous ossification and we hypothesize that abnormal embryonic cartilage that rests within the suture lines may be involved in this tumor entity. Testing of additional individuals with similar presentations is needed to confirm this finding and clarify the associated phenotypes.

Original languageEnglish (US)
Article number100006
JournalHuman Genetics and Genomics Advances
Issue number1
StatePublished - Oct 22 2020


  • IDH1
  • chondrosarcoma grade 1
  • functional validation
  • genome-wide methylation profiling
  • isocitrate dehydrogenase 1
  • mastoid bone
  • molecular dynamics simulations
  • p.Arg100Gln
  • whole-exome sequencing

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics(clinical)


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