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

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.