Genotype-phenotype correlation in hereditary multiple exostoses
- aService de Pédiatrie B et de Génétique, Hôtel Dieu, BP 69, Clermont-Ferrand, France, bUnité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, 149 rue de Sèvres, 75743 Paris Cedex 15, France
- Dr Legeai-Mallet,
- Revised 18 April 2001
- Accepted 3 May 2001
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 EXT1and 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 andEXT2 accounted for more than 90% of HME cases in our series. Among them, 27/42 cases were accounted for byEXT1 (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 withEXT1 mutations. These findings provide the first genotype-phenotype correlation in HME and will, it is hoped, facilitate the clinical management of these patients.