Whole-exome sequencing identifies de novo mutation in the COL1A1 gene to underlie the severe osteogenesis imperfecta

Abstract

Background: Osteogenesis imperfecta (OI) comprises a clinically and genetically heterogeneous group of connective tissue disorders, characterized by low bone mass, increased bone fragility, and blue-gray eye sclera. OI often results from missense mutations in one of the conserved glycine residues present in the Gly-X-Y sequence repeats of the triple helical region of the collagen type I α chain, which is encoded by the COL1A1 gene. The aim of the present study is to describe the phenotype of OI II patient and a novel mutation, causing current phenotype.

Results: We report an undescribed de novo COL1A1 mutation in a patient affected by severe OI. After performing the whole-exome sequencing in a case parent-child trio, we identified a novel heterozygous c.2317G > T missense mutation in the COL1A1 gene, which leads to p.Gly773Cys transversion in the triple helical domain of the collagen type I α chain. The presence of the missense mutation was confirmed with the Sanger sequencing.

Conclusions: Hereby, we report a novel mutation in the COL1A1 gene causing severe, life threatening OI and indicate the role of de novo mutation in the pathogenesis of rare familial diseases. Our study underlines the importance of exome sequencing in disease gene discovery for families where conventional genetic testing does not give conclusive evidence.

Fig. 1

Pedigree structure of an Estonian family affected with type II OI. DNA was collected from father (710), mother (711), brother (715), and proband (716)

Fig. 2

Results of the validation of novel COL1A1 mutation. a The Integrated Genomics Viewer image corresponding to COL1A1 exon 33–34 de novo variant c.2317G > T (GGC > TGC on „ + “strand). Genomic coordinates are given according to GRCh37/hg19 reference sequence. b Validation of the c.2317G > T by Sanger sequencing. Electropherograms of the index patient (716), her mother (711), father (710). Over 10 Gb of sequence was generated from each individual, resulting in a coverage depth of 84× for both parents and 87× for an affected child, and an unaffected brother (715) is shown. C (cytosine) is blue, T (thymine) is red, G (guanine) is black. The position of the heterozygous c.2317G > T mutation is marked by an arrow. The mutation is absent in both parents, confirming its de novo occurrence in the proband

Fig. 3

The alignment of DNA and protein sequences of COL1A1 gene is illustrated. The G to T transversion (red rectangle) in exon 33/34 at the position 2317 of the COL1A1 gene leads to Gly773 Cys substitution. At the same position, already known SNP (rs72651659) is located, but the known SNP is the G to A transition that leads to Gly773 Ser substitution