Evaluation of the patients with hereditary multiple exostosis in terms of ext1 and EXT2 gen mutations

Hereditary multiple exostosis (HME), also known as multiple osteochondroma, is a rare autosomal dominant disease, which contains malfunction in the metaphyseal region of the long bones, within the pericondrium surrounding the growth plates, i.e. in the glucosaminoglycan biosynthesis associated with skeletal and connective tissue disorders and characterized by the development of cartilage-based exophytic bone tumors. The average age range varies between 2-15 years at the onset of symptoms, and the absence of new exostosis when the growth plates are closed is typical of the disease. Exostoses are mostly benign skeletal protrusions. In approximately 0.2-5% of patients, osteochondromas can turn into life-threatening chondrosarcoma or osteosarcoma that are resistant to chemotherapy or radiotherapy by showing malignant transformation. Hereditary multiple exostosis is a genetically heterogeneous disease. Exostosin-1 (EXT1 in 8q24.11-q24.13) and Exostosin-2 (EXT2 in 11p12-p11) genes are responsible for the disease. It's shown that the majority of HME cases are associated with heterozygous dysfunction mutations in EXT1 or EXT2, most of the mutations are familial and about 10% are sporadic. In our study, it was aimed to determine EXT1 and EXT2 gene mutations in HME patients in our country, to determine new variants, to determine the genotype and phenotype relationship by examining the nature, frequency and distribution of the disease in Turkish society. Within the scope of the study, EXT1 and EXT2 genes were investigated in 26 volunteers diagnosed with HME by a new generation DNA sequence analysis method. The phenotypes and genotype findings of the cases were compared with the information in the variant databases. The characteristics of the variants detected in each case were examined in terms of their relationship with the phenotypic findings. In six cases (23%), the variant could not be detected using the method we used. In 20 cases with variants, different single nucleotide changes with deletion, insertion or nonsense (stop) / missens effect were observed. Variant was defined in 17 cases in EXT1 gene and 3 cases in EXT2 gene and all of these variants are located in the coding exon regions of genes. Information on 14 variants detected has not been found in variant databases or literature, and these variants are considered to be the newly detected variants. Seven of the variants we detected in the EXT1 gene are nucleotide deletions and all are newly detected variants. Deletions are located scattered throughout the 5 'and 3' of the gene between codon 11 and codon 705 in different regions. Two of the four stop codon variants detected have been previously reported, and the other two are from the newly detected variants. Three of the six missens variants identified were previously reported, but the other three were newly identified. In EXT2 gene variants, one is the newly detected missense variant, the second is the newly detected insertion variant and the third is the known stop codon variant. Our study is the most comprehensive study of molecular genetics HME patients in Turkey. New variants in our study will contribute to the literature. The results of this study will contribute to the development of molecular genetic diagnosis, treatment and follow-up methods in HME patients.