Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas

Abstract

Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.

Figure 1. Segregation analysis in the BCN33 and BCN29 families, in which the probands were found to bear two mutations each, one in EXT1 and one in EXT2.

Italics indicate mutations considered non-pathogenic. NA: DNA not available.

Figure 2. MLPA results for some of the patients bearing deletions of different size in the EXT1 gene.

In the Y axis, 1 and below 0.6 correspond to full dose (two copies) and half dose (one copy) of the corresponding exons, respectively. For the BCN06 family, results for different members of the family are shown. Arrow in BCN19 proband indicates the deletion of exon 8.

Figure 3. Genotype-phenotype correlations.

(A) Distribution of cases with mutations in EXT1 or EXT2 among the three clinical classes. (B) Average number of exostoses among patients bearing missense mutations in EXT1 (n = 6) or other type of mutations (nonsense and small or large insertions and deletions) in the same gene (n = 18).

Figure 4. Comparison of mutation frequencies with previous studies.

(A) Proportion of EXT1 mutation cases (dark grey), EXT2 mutation cases (light grey) and cases with no mutation identified (white). (B) Among cases with identified mutations, proportion of large rearrangements (at least one exon) are shown in dark grey, while point mutations and small insertions and deletions are shown in light grey.