J Med Genet 50:345-348 doi:10.1136/jmedgenet-2013-101567
  • New disease loci
  • Short report

Mutations in WNT1 are a cause of osteogenesis imperfecta

  1. Frank Rauch2
  1. 1Department of Human Genetics, McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada
  2. 2Genetics Unit, Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada
  1. Correspondence to Dr Frank Rauch, Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montréal, Québec, Canada H3G 1A6; frauch{at}
  • Received 29 January 2013
  • Revised 5 February 2013
  • Accepted 6 February 2013
  • Published Online First 23 February 2013


Background Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually due to dominant mutations in COL1A1 or COL1A2. Rare recessive forms of OI, caused by mutations in genes involved in various aspects of bone formation, have been described as well.

Objective To identify the cause of OI in eight children with severe bone fragility and a clinical diagnosis of OI type IV who had had negative results on COL1A1/COL1A2 Sanger sequencing.

Methods Whole exome sequencing was performed in genomic DNA samples from all eight individuals.

Results WNT1 mutations were found in four children from three families. WNT1 was the only gene where mutations were found in all of these four patients. Two siblings from a consanguineous family had a homozygous missense mutation affecting a highly conserved cysteine residue in WNT1 (c.428G>T (p.Cys143Phe)). One girl had a homozygous frameshift deletion (c.287_300del(p.Gln96Profs)). A girl from a third family was compound heterozygous for a frameshift insertion and a missense mutation affecting a conserved amino acid (c.946_949insAACA (p.Ser317Lysfs); c.1063G>T (p.Val355Phe)). All of these children had short stature, low bone density, and severe vertebral compression fractures in addition to multiple long bone fractures in the first years of life. The Wnt signalling pathway is one of the key regulators of osteoblast activity.

Conclusions Recessive inactivating mutations in WNT1 are a new cause of OI type IV.