Two novel mutations of COL1A1 in fetal genetic skeletal dysplasia of Chinese

Abstract

Background Skeletal disorders, which have great genotypic and phenotypic varieties, are a considerable challenge to differentiate these diseases and provide a definitive prenatal diagnosis or pre‐implantation. The present study aims to identify the causative mutation in two unrelated outbred Han–Chinese families. Method Two short‐limb fetuses were referred to our hospital. Genomic DNA was extracted from the amniotic fluid of the short‐limb fetuses and from peripheral blood of their parents. To identify the causative gene, next‐generation‐based target capture sequencing was performed on these two fetuses, followed by Sanger Sequencing in unrelated healthy controls. Segregation analysis of the candidate variant was performed in parents by using Sanger sequencing. The mutations were analyzed by SIFT, PolyPhen and Provean. Results We found that fetal genetic skeletal dysplasia was confirmed according to the correlations between genetic mutations and phenotypes in two Chinese families. Targeted next generation sequencing was performed to screen causative mutations in patients. Two novel heterozygous mutations COL1A1 c.1706 G > C (p. G569A) and c.3307 G > A (p. G1103S) were respectively identified. The results suggested that COL1A1 novel mutations were in highly conserved glycine residues present in the Gly‐X‐Y sequence repeats of the triple helical region of the collagen type I α chain, which was responsible for Osteogenesis Imperfecta. The presence of the missense mutation was also confirmed with the Sanger sequence. These two mutations were predicted to be pathogenic by SIFT, PolyPhen and Provean. Conclusion Our findings showed that the mutations of COL1A1 may play important roles in fetal genetic skeletal dysplasia in Chinese patients. Exome sequencing enhances the accurate diagnosis in utero then provides appropriate genetic counseling.

Combined exome sequencing and deep phenotyping in highly selected fetuses with skeletal dysplasia during the first and second trimesters improves diagnostic yield

“…Among them, cases 7 and 8 were reported by Li et al. in 2020 29 . Two cases (22 and 23) presented with compound heterozygous mutations inherited from the parents with an implied 25% of recurrence risk.…”

Prenatal diagnosis of genetic aberrations in fetuses with short femur detected by ultrasound: A prospective cohort study

“…Fourth, for the fetuses with extremely short femur without G380R mutation of FGFR3 , further monogenic testing was not performed. Recently, next‐generation sequencing (NGS) has been applied in prenatal diagnosis for fetuses with structural anomalies including skeletal dysplasia 23,45–49 . Any additional diagnoses so derived will more accurately define the reproductive recurrence risks.…”

Case Report: A Novel COL1A1 Missense Mutation Associated With Dentineogenesis Imperfecta Type I

“…Ther. 9:221. doi: 10.1186/s13287-018-0965-3 Yi, Q., Feng, X., Zhang, C., Wang, X., Wu, X., Wang, J., et al (2020). Comparison of dynamic mechanical properties of dentine between deciduous and permanent teeth.…”

“…OI can affect the life quality of patients with the disease because the main causative gene, type I collagen ( COL1A1 ), encodes a major structural protein of dentine, bone, and other fibrous tissues (Wang et al, 2019 ; Li et al, 2020 ). Therefore, a mutation in type I collagen gene COL1A1 gene might alter the collagen fibrils, which may affect the formation and stability of bone and dentine minerals and, finally, result in a variety of abnormal phenotypes (Marom et al, 2020 ).…”