title: 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.
authors.affiliation: Clinic of Traumatology and Orthopaedics, University of Tartu, Puusepa 8, 51014, Tartu, Estonia. Katre.maasalu@kliinikum.ee.|Clinic of Traumatology and Orthopaedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia. Katre.maasalu@kliinikum.ee.
authors.forename: Katre
authors.initials: K
authors.lastname: Maasalu
authors.affiliation: Estonian Genome Centre, University of Tartu, Riia 23b, Tartu, 51010, Estonia. tiitn@ebc.ee.|Institute of Molecular and Cell Biology, University of Tartu, Riia 23b, Tartu, 51010, Estonia. tiitn@ebc.ee.
authors.forename: Tiit
authors.initials: T
authors.lastname: Nikopensius
authors.affiliation: Department of Pathophysiology, University of Tartu, Ravila 19, Tartu, 50411, Estonia. Sulev.Koks@ut.ee.
authors.forename: Sulev
authors.initials: S
authors.lastname: Kõks
authors.affiliation: Estonian Genome Centre, University of Tartu, Riia 23b, Tartu, 51010, Estonia. margit.noukas@ut.ee.|Institute of Molecular and Cell Biology, University of Tartu, Riia 23b, Tartu, 51010, Estonia. margit.noukas@ut.ee.
authors.forename: Margit
authors.initials: M
authors.lastname: Nõukas
authors.affiliation: Estonian Genome Centre, University of Tartu, Riia 23b, Tartu, 51010, Estonia. mart.kals@ut.ee.
authors.forename: Mart
authors.initials: M
authors.lastname: Kals
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Riia 23b, Tartu, 51010, Estonia. Ele.prans@ut.ee.
authors.forename: Ele
authors.initials: E
authors.lastname: Prans
authors.affiliation: Clinic of Traumatology and Orthopaedics, University of Tartu, Puusepa 8, 51014, Tartu, Estonia. Lida.zhytnik@gmail.com.
authors.forename: Lidiia
authors.initials: L
authors.lastname: Zhytnik
authors.affiliation: Estonian Genome Centre, University of Tartu, Riia 23b, Tartu, 51010, Estonia. andres.metspalu@ut.ee.|Institute of Molecular and Cell Biology, University of Tartu, Riia 23b, Tartu, 51010, Estonia. andres.metspalu@ut.ee.|Estonian Biocentre, Riia 23b, 51010, Tartu, Estonia. andres.metspalu@ut.ee.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Clinic of Traumatology and Orthopaedics, University of Tartu, Puusepa 8, 51014, Tartu, Estonia. Aare.Martson@kliinikum.ee.|Clinic of Traumatology and Orthopaedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia. Aare.Martson@kliinikum.ee.
authors.forename: Aare
authors.initials: A
authors.lastname: Märtson
mesh_terms: D000328:Adult; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D059472:Exome / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain