Genotype-phenotype correlation in hereditary multiple exostoses.
Hereditary multiple exostoses (HME) is a genetically heterogeneous autosomal dominant disorder characterised by the development of bony protuberances mainly located on the long bones. Three HME loci have been mapped to chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes encode glycosyltransferases involved in biosynthesis of heparan sulphate proteoglycans. Here we report on a clinical survey and mutation analysis of 42 HME French families and show that EXT1 and EXT2 accounted for more than 90% of HME cases in our series. Among them, 27/42 cases were accounted for by EXT1 (64%, four nonsense, 19 frameshift, three missense, and one splice site mutations) and 9/42 cases were accounted for by EXT2 (21%, four nonsense, two frameshift, two missense, and one splice site mutation). Overall, 31/36 mutations were expected to cause loss of protein function (86%). The most severe forms of the disease and malignant transformation of exostoses to chondrosarcomas were associated with EXT1 mutations. These findings provide the first genotype-phenotype correlation in HME and will, it is hoped, facilitate the clinical management of these patients.
Francannet
C
C
Service de Pédiatrie B et de Génétique, Hôtel Dieu, BP 69, Clermont-Ferrand, France.
Cohen-Tanugi
A
A
Le Merrer
M
M
Munnich
A
A
Bonaventure
J
J
Legeai-Mallet
L
L
D017668:Age of Onset; D002675:Child, Preschool; D002813:Chondrosarcoma / Q000235:genetics / Q000473:pathology; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004252:DNA Mutational Analysis; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005602:France; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D000099065:Exostosin 2; D000099058:Exostosin 1
D011506:Proteins; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1; D000099065:Exostosin 2