Identification of a Rare Variant of c.1777G>A (p.G593S) in the COL1A1 Gene as the Etiology of Recurrent Osteogenesis Imperfecta by Whole-Exome Sequencing

BACKGROUND: Osteogenesis imperfecta (OI) is a rare heterogeneous disorder typically featured by fragile bones and susceptibility to fracture. The aim of the present study was to explore the genetic etiology of familial recurrent OI and the genotype–phenotype correlation. METHODS: Karyotyping, chromosomal microarray analysis, and whole-exome sequencing (WES) were performed to determine the genetic etiology of OI in the enrolled family. Western blotting analysis was carried out using the fetal skin tissue for type I collagen production analysis. RESULTS: At the first pregnancy, a c.1777G>A mutation in the COL1A1 gene was detected in the fetus who exhibited skeletal dysplasia. In this second pregnancy, severe fetal skeletal dysplasia was also presented without significant chromosomal abnormality detected by karyotype and chromosomal microarray analysis in the fetus. Further WES results demonstrated a de novo missense mutation of c.1777G>A (p.G593S) in the fetus, which was classified as a pathogenic variant according to the ACMG guidelines. The recurrent mutation in the two fetuses hinted at the possible existence of gonadal mosaicism in the parents, while no mutation in the COL1A1 gene was identified in the DNA from the father's sperm. In addition, Western blot results demonstrated no reduced type I procollagen production in the affected fetus compared with the age-matched controls. CONCLUSIONS: To the best of our knowledge, this is the first study that identified a rare variant of c.1777G>A in the COL1A1 gene that led to recurrent OI in the Chinese population. Additionally, we believe that this rare variant of c.1777G>A in the COL1A1 gene will lead to OI type II. The results of the present study further verify the application value of WES in identifying fetuses with ultrasound anomalies.