Co-occurrence of heterozygous mutations in COL1A1 and SERPINF1 in a high-risk pregnancy complicated by osteogenesis imperfecta

Mutations in several genes, including SERPRINF1 and COL1A1, have been associated with the development of osteogenesis imperfecta (OI). Here, we reported the co-occurrence of a rare heterozygous variant (c.167C>G p.Ala56Gly) in SERPRINF1 and a novel heterozygous mutation (c.1634G>A p.Gly545Asp) in COL1A1 in a foetus with a severe form of OI. Bioinformatics modelling revealed that the effect of the mutation on SPERINF1 is neutral. In contrast, the mutation in COL1A1 is deleterious. It is predicted to cause distortion of the α (1) chain of the type I collagen and results in structural instability of the protein. Therefore, a novel dominant variant of COL1A1 likely underlies the severe foetal pathology observed, although we do not exclude the possibility that the heterozygous mutations in SERPINF and COL1A1 may interact and co-ordinately cause pathogenesis. This novel COL1A1 mutation is recommended to be included in the diagnostic panels for OI.

PCR-HRM Analysis for Gene Mutation Screening in a Child with Osteogenesis Imperfecta / 天津医药

Objective To investigate COL1A1 gene mutation by PCR-high resolution melting (PCR-HRM) and an-alyze the correlation between genotype and clinical phenotype in a child (proband) with osteogenesis imperfecta (OI). Methods The family history of OI pedigree along with the clinical data was collected. Blood samples from the proband and his family members, as well as 50 normal controls, were collected. The mutation of COL1A1 gene was screened using PCR-HRM and validated by the gene sequence. Results The detection of PCR-HRM showed the abnormal result of COL1A1 17 exon in proband with a lower melting temperature (Tm) value than that of normal controls by 0.4℃. There were signifi-cant differences in the standardization melting curve and the different melting curve between the proband and the normal controls. The sequencing result was c.1138G>A, which meant that cDNA of 1138 base G mutation into A. The mutations transformed the amino acid glycine into a serine at amino acid 380(P. Gly 380 Ser), which resulted in missense mutations. The proband’s father and grandmother had the same mutation of COL1A1 gene. The mutation was not found in the proband’s mother and normal controls. There was no report for such mutation in Chinese population. Pedigree analysis showed the fami-ly genetic characteristics of autosomal dominant inheritance. The proband was clinically diagnosed as OI type Ⅳwith more severe clinical phenotype. Conclusion PCR-HRM analysis is a new effective method for genetic screening of OI. COL1A1 mutation of c.1138G>A is a newly discovered mutation in Chinese population. Gly replaced inαhelical domain may lead to a more severe clinical phenotype.