Dataset Information

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.

SUBMITTER: Higuchi Y

PROVIDER: S-EPMC8222851 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Osteogenesis imperfecta (OI), mainly caused by structural abnormalities of type I collagen, is a hereditary rare disease characterized by increased bone fragility and reduced bone mass. Clinical manifestations of OI mostly include multiple repeated bone fractures, thin skin, blue sclera, hearing loss, cardiovascular and pulmonary system abnormalities, triangular face, dentinogenesis imperfecta (DI), and walking with assistance. Currently, 20 causative genes with 18 subtypes have been identified for OI, of them, variations in COL1A1 and COL1A2 have been demonstrated to be major causative factors to OI. However, the complexity of the bone formation process indicates that there are potential new pathogenic genes associated with OI. To comprehensively explore the underlying mechanism of OI, we conducted association analysis between genotypes and phenotypes of OI diseases and found that mutations in COL1A1 and COL1A2 contributed to a large proportion of the disease phenotypes. We categorized the clinical phenotypes and the genotypes based on the variation types for those 155 OI patients collected from literature, and association study revealed that three phenotypes (bone deformity, DI, walking with assistance) were enriched in two variation types (the Gly-substitution missense and groups of frameshift, nonsense, and splicing variations). We also identified four novel variations (c.G3290A (p.G1097D), c.G3289C (p.G1097R), c.G3289A (p.G1097S), c.G3281A (p.G1094D)) in gene COL1A1 and two novel variations (c.G2332T (p.G778C), c.G2341T (p.G781C)) in gene COL1A2, which could potentially contribute to the disease. In addition, we identified several new potential pathogenic genes (ADAMTS2, COL5A2, COL8A1) based on the integration of protein-protein interaction and pathway enrichment analysis. Our study provides new insights into the association between genotypes and phenotypes of OI and novel information for dissecting the underlying mechanism of the disease.