Genotype-phenotype correlation in hereditary multiple exostoses

• Published in: Journal of medical genetics Vol. 38; no. 7; pp. 430 - 434
• Main Authors: Francannet, C, Cohen-Tanugi, A, Le Merrer, M, Munnich, A, Bonaventure, J, Legeai-Mallet, L
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-07-2001; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Age of Onset; Analysis; Biological and medical sciences; Child, Preschool; Chondrosarcoma; Chondrosarcoma - genetics; Chondrosarcoma - pathology; Chromosomes; Chromosomes, Human, Pair 11 - genetics; Chromosomes, Human, Pair 8 - genetics; Diseases of the osteoarticular system; DNA Mutational Analysis; Exostoses, Multiple Hereditary - genetics; Exostoses, Multiple Hereditary - pathology; Exostosis; EXT1; EXT2; Female; France; Genetic aspects; Genetic Heterogeneity; Genotype; Genotype & phenotype; hereditary multiple exostoses; Humans; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mutation; Mutation - genetics; N-Acetylglucosaminyltransferases - genetics; Original; Patients; Pedigree; Phenotype; Proteins - genetics; France; United States; Human; Chondrosarcoma; Multiple; Family study; Pathogenesis; Diseases of the osteoarticular system; Genotype; Malignant tumor; Genetic determinism; Genetic disease; Cartilage; Phenotype; Gene; Mutation; Osteochondrodysplasia; Multiple cartilaginous exostosis
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.38.7.430

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.