Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA)

Lisenka E L M Vissers, Virginia Fano, Diego Martinelli, Belinda Campos-Xavier, Domenico Barbuti, Tae Joon Cho, Ahmet Dursun, Ok Hwa Kim, Sun Hee Lee, Giuseppina Timpani, Gen Nishimura, Sheila Unger, Jörn Oliver Sass, Joris A. Veltman, Han G. Brunner, Luisa Bonafé, Carlo Dionisi-Vici, Andrea Superti-Furga

Research output: Contribution to journalArticlepeer-review


We used exome sequencing of blood DNA in four unrelated patients to identify the genetic basis of metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid (MC-HGA), a rare entity comprising severe chondrodysplasia, organic aciduria, and variable cerebral involvement. No evidence for recessive mutations was found; instead, two patients showed mutations in IDH1 predicting p.R132H and p.R132S as apparent somatic mosaicism. Sanger sequencing confirmed the presence of the mutation in blood DNA in one patient, and in blood and saliva (but not in fibroblast) DNA in the other patient. Mutations at codon 132 of IDH1 change the enzymatic specificity of the cytoplasmic isocitrate dehydrogenase enzyme. They result in increased D-2-hydroxy-glutarate production, α-ketoglutarate depletion, activation of HIF-1α (a key regulator of chondrocyte proliferation at the growth plate), and reduction of N-acetyl-aspartyl-glutamate level in glial cells. Thus, somatic mutations in IDH1 may explain all features of MC-HGA, including sporadic occurrence, metaphyseal disorganization, and chondromatosis, urinary excretion of D-2-hydroxy-glutaric acid, and reduced cerebral myelinization.

Original languageEnglish
Pages (from-to)2609-2616
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Issue number11
Publication statusPublished - Nov 2011


  • D-2-hydroxyglutaric acidura
  • Isocitrate dehydrogenase
  • Metaphyseal chondromatosis
  • Mosaicism
  • Somatic mutation
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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