Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr 8:10:816090.
doi: 10.3389/fped.2022.816090. eCollection 2022.

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

Jianlong Zhuang  1 , Chunnuan Chen  2 , Yu'e Chen  3 , Qi Luo  4 , Yuanbai Wang  1 , Yuying Jiang  1 , Shuhong Zeng  1 , Yingjun Xie  5   6 , Dongmei Chen  7
Affiliations

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

Jianlong Zhuang et al. Front Pediatr. .

Abstract

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.

Keywords: COL1A1; chromosomal microarray analysis; osteogenesis imperfecta; type I collagen; whole-exome sequencing.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pedigree information and ultrasound anomalies detected in the fetus. (A) Pedigree information in this family. (B,C) Ultrasound results showing that the bilateral humerus of the fetus was slightly curved. (D) The ultrasound results revealing that the left femur of the fetus was shorter and bent into an angle. (E) The ultrasound results suggested that the right femur of the fetus was shorter and slightly curved. The arrows indicate the anomalies.
Figure 2
Figure 2
Detection of the variant by whole-exome sequencing (WES) and verification by Sanger sequencing in the family. (A) The WES detection results demonstrated a de novo variant of c.1777G>A in exon 26 of the COL1A1 gene in the fetus. (B) Sanger sequencing verified the variant detected by WES in the fetus. (C,D) Neither parent carried the c.1777G>A mutation in the COL1A1 gene by Sanger sequencing.
Figure 3
Figure 3
Type I collagen production assay using Western blot analysis in the fetus. (A) The protein was extracted from the fetal abortion skin tissue for Western blot analysis, and three age-matched skin tissues without the COL1A1 mutation were used as the controls. (B) No significant reduction of the intracellular type I collagen product was observed in the proband compared with the control group.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, et al. . Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. (2007) 28:209–21. 10.1002/humu.20429 - DOI - PMC - PubMed
    1. Marini JC, Forlino A, Bächinger HP, Bishop NJ, Byers PH, Paepe A, et al. . Osteogenesis imperfecta. Nat Rev Dis Primers. (2017) 3:17052. 10.1038/nrdp.2017.52 - DOI - PubMed
    1. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. (1979) 16:101–16. 10.1136/jmg.16.2.101 - DOI - PMC - PubMed
    1. Lindahl K, Åström E, Rubin CJ, Grigelioniene G, Malmgren B, Ljunggren Ö, et al. . Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. Eur J Hum Genet. (2015) 23:1042–50. 10.1038/ejhg.2015.81 - DOI - PMC - PubMed
    1. Sillence DO, Rimoin DL, Danks DM. Clinical variability in osteogenesis imperfecta-variable expressivity or genetic heterogeneity. Birth Defects Orig Artic Ser. (1979) 15:113–29. - PubMed