Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands

Abstract

Background: Osteogenesis imperfecta (OI) is a rare connective-tissue disorder characterized by bone fragility. Approximately 90% of all OI cases are caused by variants in COL1A1 or COL1A2. Additionally, IFITM5 variants are responsible for the unique OI type 5. We previously analyzed COL1A1/2 variants in 22 Japanese families with OI through denaturing high-performance liquid chromatography screening, but our detection rate was low (41%).

Methods: To expand the genotype-phenotype correlations, we performed a genetic analysis of COL1A1/2 and IFITM5 in 96 non-consanguineous Japanese OI probands by Sanger sequencing.

Results: Of these individuals, 54, 41, and 1 had type 1 (mild), type 2-4 (moderate-to-severe), and type 5 phenotypes, respectively. In the mild group, COL1A1 nonsense and splice-site variants were prevalent (n = 30 and 20, respectively), but there were also COL1A1 and COL1A2 triple-helical glycine substitutions (n = 2 and 1, respectively). In the moderate-to-severe group, although COL1A1 and COL1A2 glycine substitutions were common (n = 14 and 18, respectively), other variants were also detected. The single case of type 5 had the characteristic c.-14C>T variant in IFITM5.

Conclusion: These results increase our previous detection rate for COL1A1/2 variants to 99% and provide insight into the genotype-phenotype correlations in OI.

Keywords: COL1A1; COL1A2; IFITM5; Osteogenesis imperfecta; variant.

FIGURE 1

Variant spectra of COL1A1 and COL1A2. Symbols above the box represent the variants in the mild OI group. Symbols below the box represent the variants in the moderate‐to‐severe OI group. Aligned symbols represent the same variant