Zayed Al-Zayed1,2, Roua A Al-Rijjal3, Lamya Al-Ghofaili2, Huda A BinEssa3, Rajeev Pant1, Anwar Alrabiah1,2, Thamer Al-Hussainan1,2, Minjing Zou3, Brian F Meyer3, Yufei Shi4. 1. Department of Orthopedics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 2. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 3. Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia. 4. Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia. yufei@kfshrc.edu.sa.
Abstract
BACKGROUND: Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients. AIM OF STUDY: We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families. METHODS: Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron-exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis. RESULTS: EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients. CONCLUSION: EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.
BACKGROUND: Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients. AIM OF STUDY: We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families. METHODS: Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron-exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis. RESULTS: EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients. CONCLUSION: EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.
Authors: Ayşe Nurcan Cebeci; Minjing Zou; Huda A BinEssa; Ali S Alzahrani; Roua A Al-Rijjal; Anwar F Al-Enezi; Futwan A Al-Mohanna; Etienne Cavalier; Brian F Meyer; Yufei Shi Journal: J Clin Endocrinol Metab Date: 2020-06-01 Impact factor: 5.958
Authors: Ewelina Bukowska-Olech; Wiktoria Trzebiatowska; Wiktor Czech; Olga Drzymała; Piotr Frąk; Franciszek Klarowski; Piotr Kłusek; Anna Szwajkowska; Aleksander Jamsheer Journal: Front Genet Date: 2021-12-10 Impact factor: 4.599