Mutant EXT1 in Taiwanese Patients with Multiple Hereditary Exostoses.
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ABSTRACT: Background
Multiple hereditary exostoses (MHE) is characterized by multiple benign projections of bone capped by cartilage, most numerous in metaphyses of long bones. HME are usually inherited in autosomal dominant mode, chief genes EXT1 and EXT2.Methods
Two MHE patients were identified from clinic and enrolled in genetic study, complete coding regions of EXT1 and EXT2, including intron/exon boundaries, sequenced via DNA samples drawn from participants.Results
DNA sequencing revealed mutant EXT1 gene in both cases, within which frame-shift mutation c.447delC (p.Ser149fsX156) in exon1 and nonsense mutation c.2034T>G (p.Tyr678X) in exon10, emerged. Neither mutation was detected in control group.Conclusions
Our results extended the spectrum of EXT1 mutations, revealing similar incidence of EXT1 and EXT2 in Taiwanese MHE patients.
SUBMITTER: Lin WD
PROVIDER: S-EPMC4265008 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To identify the pathogenic gene variation in a Chinese family with Hereditary Multiple Exostoses (HME). By examining blood-sourced DNA and clinical manifestations of the proband and his family members, the whole exome sequencing (WES) and Sanger sequencing were used to detect possibly pathogenic mutations. A novel heterozygous mutation (c.325dup) was identified in exon 1 of the exostosin 1 (EXT1) gene from the proband and the affected family members. And we found this mutation was absent in all the unaffected family members. This c.325dup mutation is in the exon 1 domain of the EXT1 gene and the change of p.C109Lfs*80 cause the early termination of protein translation. The identification of the novel frameshift insertion mutation (c.325dup) expands the mutation spectrum of HME, which provides new evidence for HME diagnosis.
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Project description:Multiple hereditary exostoses (MHE) is a rare autosomal dominant skeletal disorder with a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of MHE using our own scoring system and analyzed the risk factors associated with severe clinical phenotypes. In this study, 43 patients from 30 families were analyzed. The mutations were identified by direct sequencing of polymerase chain reaction-amplified genomic DNA or by multiplex ligation-dependent probe amplification. According to a new scoring system devised by the authors, the severity of the phenotype was assessed as mild, moderate, or severe based on the deformity of each segment, number of exostoses, leg length discrepancy, and functional limitations. Of 43 patients from 30 families, 39 patients (90.7%) and 24 families (80%) presented with EXT1 or EXT2 mutations. Patients with EXT1 mutations had a significantly worse phenotype than that of patients with EXT2 mutations or without any detectable mutation. The mean clinical score of patients with an EXT1 mutation (5.76; range, 2.0-8.0; SD = 1.60) was higher than that of patients with an EXT2 mutation (4.06; range, 2.0-7.0; SD = 1.47) or of those without any detectable mutation (4.63; range, 3.0-6.0; SD = 1.44; p = 0.005). According to our classification system, more patients with EXT1 mutations had 'severe disease' than those with EXT2 mutations. Deformity scores were also higher in patients with EXT1 mutations (p = 0.018). In the multivariate analysis, the deformity score was found to be associated with the 'severe' class (p = 0.031). In conclusion, 90.7% of patients with MHE showed EXT mutations. Our scoring system showed reliable results. We suggest that the extent of deformity is an important factor in determining the phenotype of MHE and close monitoring for the development of severe disease is recommended in patients with high deformity scores.
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