Gene mutation screening and the genotype-phenotype correlation of hereditary multiple exostoses

Abstract

Objective To establish the method of gene mutation screening for HME and investigate the relationship between genotype and clinical phenotype in HME patients. Methods Fifteen cases of HME probands were divided into the following four subgroups: mild (M) and severe ( Ⅰ S, Ⅱ S, Ⅲ S) according to the clinical diagnosis. DNA samples were obtained from the probands and family members. All of the EXT1 and EXT2 gene exons and their boundary sequences were amplified by PCR, and sequenced by directsequencing. Then the relationship between the genotypes and clinical phenotype was analyzed. Results Among the fifteen cases of HME probands, nine harbored EXT1 gene mutation, while the other 6 were positive for EXT2 gene mutation. Moreover, six novel mutations in EXT1 gene, including I8 + 2T ＞ G, c. 1182delG,c. 1108G ＞T(p. E370X) ,c. 335delA,c. 361C ＞T(p. Q121X) and c. 1879_1881delCAC were identified. In 9 patients with EXT1 gene mutation, 2 (22. 2% ) were M-type, 2 (22. 2% ) were Ⅰ S -type, 4 (44. 4% )were Ⅱ S-type,and 1 ( 11.1% ) was ⅢS-type. Whereas, 5 cases (83.3%) were M-type and only one case was Ⅱ S-type( 16. 7% ) in 6 patients with EXT2 gene mutation. Conclusions An accurate and simple gene diagnostic method for HME was established. Six novel EXT1 gene mutations, including I8 + 2T ＞ G,c. 1182delG, c. 1108G ＞T(p. E370X), c. 335delA, c. 361C ＞T(p. Q121X)and c. 1879_1881delCAC were identified as well. The clinical phenotype of the patients with EXT1 gene mutation was more severe compared to those with EXT2 gene mutations. Key words: Exostoses, multiple hereditary; N-Acetylglucosaminyltransferase; Genes, tumor suppressor; Mutation; Genotype; Phenotype