EVALUATION OF LOCUS HETEROGENEITY AND EXT1 MUTATIONS IN 34 FAMILIES WITH HEREDITARY MULTIPLE EXOSTOSES

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by growth of benign bone tumors. Three chromosomal loci have been implicated in this genetically heterogeneous disease: EXT1 a t 8q24, EXT2 at 11p13, and EXT3 on 19p. EXT1 and EXT2 were recently cl oned. We evaluated 34 families with EXT to estimate the proportion of disease attributable to EXT1, EXT2, and EXT3 and to investigate the sp ectrum of EXT1 mutations. Linkage analyses combined with heterogeneity testing provides strong evidence in favor of linkage of disease to bo th chromosomes 8 and 11, but does not support evidence of linkage to c hromosome 19 in this data set. The 11 EXT1 exons were PCR-amplified an d sequenced in all 11 isolated cases and in 20 of the 23 familial case s. Twelve different novel EXT1 mutations were detected, including 5 fr ame-shift deletions or insertions, 1 codon deletion, and 6 single base pair substitutions distributed across 8 of the exons. Only 2 of the m utations were detected in more than one family. Three mutations affect sites in which alterations were previously reported. Nonchain termina ting missense mutations were identified in codons 280 and 340, both co ding for conserved arginine residues. These residues may be crucial to the function of this protein, Although the prevalence of EXT has been estimated to be approximately 1/50,000 individuals, the disease has b een reported to occur much more frequently in the Chamorro natives on Guam, Our detection of an EXT1 mutation in one Chamorro subject will a llow investigation of a possible founder effect in this population. Co mbined mutational and heterogeneity analyses in this set of families w ith multiple exostoses suggest that 66% of our total sample, including 45% of isolated and 77% of familial cases, are attributable to abnorm alities in EXT1. (C) 1998 Wiley-Liss, Inc.