Genetic diagnosis of six fetuses with osteogenesis imperfecta

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Objective To analyze gene mutations and the etiology of six fetuses with osteogenesis imperfecta detected by prenatal ultrasonography. Methods From March 2016 to May 2017, six gravidas of singleton pregnancy and their fetuses that were diagnosed with osteogenesis imperfecta by prenatal ultrasonography were enrolled in this study. Gravida 1 came to the Center of Prenatal Diagnosis of the First Affiliated Hospital of Zhengzhou University for prenatal diagnosis, while the other five were referred to that center after termination to identify genetic defects with their fetal tissues. Next-generation sequencing technology was carried out for exome sequencing in the genomes of six fetuses. Suspected mutations were confirmed by polymerase chain reaction and Sanger sequencing. Two hundred unrelated healthy individuals were analyzed with Sanger sequencing for validation of novel mutations. Results Fetus 1 carried a heterozygous mutation in collagen, typeⅠ, alpha-1 (COL1A1) gene, c.724G>C(p.Gly242Arg), which was found in the mother and brother but not in the father. Fetus 2 carried a known heterozygous mutation in COL1A1 gene, c.2461G>A(p.Gly821Ser), which was found in the mother but not in the father. Four heterozygous mutations, c.2282G>A(p.Gly761Asp), c.1002+5G>A in COL1A1 gene, c.1774G>A(p.Gly592Ser) and c.3277G>T(p.Gly1093Cys) in collagen, typeⅠ, alpha-2 (COL1A2) gene, were respectively carried by fetuses 3 to 6, but not by their parents. Mutations of c.724G>C(p.Gly242Arg), c.2282G>A (p.Gly761Asp) and c.1002+5G>A in COL1A1 gene and c.3277G>T (p.Gly1093Cys) in COL1A2 gene were four novel mutations, which were not found in the 200 unrelated healthy individuals. The mother of fetus 1 who was highly suspected with osteogenesis imperfecta selected to continue the pregnancy because the family members had mild symptoms. After delivery, cord blood was collected for genetic test and the result was consistent with that of prenatal genetic diagnosis. Fetus 1 had no fractures during a six-month follow-up after birth. Conclusions Mutations in the COL1A1 and COL1A2 genes may be the etiology of osteogenesis imperfecta in these six fetuses. Results of this study could enrich the data on COL1A1 and COL1A2 mutations relating to osteogenesis imperfecta, and provide a basis for genetic counseling. Key words: Osteogenesis imperfecta; Collagen typeⅠ; Mutation; Prenatal diagnosis; Genetic testing