How to Cite this Article: Vissers LELM, Fano V, Martinelli D, Campos-Xavier B, Barbuti D, Cho T-J, Dursun A, Kim OH, Lee SH, Timpani G, Nishimura G, Unger S, Sass JO, Veltman JA, Brunner HG, Bonafé L, Dionisi-Vici C, Superti-Furga A. 2011. Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA). Am J Med Genet Part A 155: 2609–2616.
Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA)†
Article first published online: 5 OCT 2011
Copyright © 2011 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 155, Issue 11, pages 2609–2616, November 2011
How to Cite
Vissers, L. E.L.M., Fano, V., Martinelli, D., Campos-Xavier, B., Barbuti, D., Cho, T.-J., Dursun, A., Kim, O. H., Lee, S. H., Timpani, G., Nishimura, G., Unger, S., Sass, J. O., Veltman, J. A., Brunner, H. G., Bonafé, L., Dionisi-Vici, C. and Superti-Furga, A. (2011), Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA). Am. J. Med. Genet., 155: 2609–2616. doi: 10.1002/ajmg.a.34325
- Issue published online: 20 OCT 2011
- Article first published online: 5 OCT 2011
- Manuscript Accepted: 7 SEP 2011
- Manuscript Received: 23 JUN 2011
- Swiss National Science Foundation. Grant Number: FN 310030-132940/BONAFE Luisa
- Fonds de Recherche du Departement Medico-Chirurgical de Pédiatrie, CHUV
- Netherlands Organization for Health Research and Development. Grant Numbers: 917-66-363, 911-08-025, 916-86-016
- Leenaards Foundation
- whole-genome sequencing;
- metaphyseal chondromatosis;
- D-2-hydroxyglutaric acidura;
- somatic mutation;
- isocitrate dehydrogenase
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. © 2011 Wiley Periodicals, Inc.