Genotype in patients with osteogenesis imperfecta using a targeted exome sequencing: correlation with phenotype

Takuo Kubota; Yasuhisa Ohata; Varoona Bizaoui-Auffret; Nobutoshi Nawa; Hirofumi Nakayama; Keiko Yamamoto; Makoto Fujiwara; Taichi Kitaoka; Satoshi Takakuwa; Noriyuki Namba; Keiichi Ozono

doi:10.1530/boneabs.4.P16

Objectives: Osteogenesis imperfecta (OI) is a relatively common skeletal dysplasia characterized by bone fragility, mainly resulting from mutations in the COL1A1 and COL1A2 genes. Phenotype–genotype correlation is not fully uncovered in OI. Additionally, more than ten genes have been found to be responsible for OI. In the current study, we determine mutations in patients with OI using a targeted exome sequencing and examine a phenotype–genotype correlation.

Methods: Twenty-two patients with OI clinically diagnosed were included in our study: type I, 13; III, 4; IV, 5. The medium age was 4.2 years; height SDS, −1.7; annualized fracture rate, 0.6; lumbar bone mineral density SDS, −2.9. A customized panel for the targeted exome sequencing constituted 34 genes associated bone strength, including 14 causative genes in OI. DNA from blood was subjected to the targeted exome sequencing, and variants were annotated. Sanger sequencing was carried out to confirm identified mutations and to determine regions uncovered or unread by the targeted exome sequencing. This study was approved by the IRB, and informed consents were obtained from patients and/or their guardians.

Results: Twelve mutations were found in the COL1A1 gene, whereas four in the COL1A2 gene. Other mutations were not confirmed in this study. Based on the types of mutations, non-sense mutations were detected in four patients; frameshift, 3; splice site, 4; glycine substitution, 5. Phenotypes were evaluated between glycine substitution mutations and non-functional mutations such as non-sense and frameshift. Annualized fracture rates were increased in patients with the glycine substitution mutations (4.7) compared to those with the non-functional ones (0.5). Patients with the glycine substitution (0.2 years) were younger than those with the non-functional mutations (4.7). All of the OI patients with the non-functional mutations were classified as type I and experienced no fetal bone deformities. Annualized fracture rates tended to be higher, but not significantly, in patients with the glycine substitution (0.5) than those with the non-functional mutations (0) during the year following the initiation of pamidronate treatment.

Conclusion: Phenotype and genotype are correlated in patients with OI to some extent. Further investigations are needed to fully uncover these correlations.

Disclosure: The authors declared no competing interests.

Bone Abstracts

P16