Background: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous rare disorder characterized by variable symptoms including predisposition to fractures. OI has been associated with mutations affecting the synthesis of type I collagen. However, the new technologies have permitted the identification of other responsible genes which are in the collagen metabolic pathway, while others are not.
Objective: Characterize the genotype of patients with OI.
Methods: Study by Next Generation Sequencing (5500XL SOLID) the OI related genes: COL1A1, COL1A2, CRTAP, FKBP10, LEPRE1, PPIB, SERPINF1, SERPINH1 and SP7 and confirmation of the identified mutations by PCR and Sanger sequencing.
Results and discussion: Patient 1 (male with severe phenotype of OI). Heterozygous carrier of the COL1A2 mutation NM_000089.3: c.1207G >T (p.Gly403Cys). This mutation has not been previously described. The theoretical predictors suggest pathogenicity, which is consistent with the clear phenotype of OI in this patient. Patient 2 (girl with mild phenotype of OI). Heterozygous carrier of the COL1A1 mutation NM_000088.3: c.572G > C (p.Gly191Ala). This mutation appears in The Human Gene Mutation Database associated with cervical artery dissection and the missense predictions indicate pathogenicity. Patients 3 and 4 (siblings with moderate phenotype of OI). Both girls are heterozygous carriers of the COL1A1 mutation NM_000088.3: c.2T > C (p.Met1?). This mutation has not been previously described and there is not data of associated phenotype. This variation affects the translation initiation codon of the mRNA which indicates pathogenicity.
Conclusion: The genetic analysis confirmed the diagnosis of OI in all the patients studied. These results allowed a better classification of patients and permitted an adequate genetic counselling. One COL1A1 and one COL1A2 novel mutations are described.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology