Genotype-phenotype analysis of a rare type of osteogenesis imperfecta in four Chinese families with WNT1 mutations

Clin Chim Acta. 2016 Oct 1;461:172-80. doi: 10.1016/j.cca.2016.07.012. Epub 2016 Jul 20.


Backgrounds: Osteogenesis imperfecta (OI) is a rare inherited disease characterized by increased bone fragility and vulnerability to fractures. Recently, WNT1 is identified as a new candidate gene for OI, here we detect pathogenic mutations in WNT1 and analyze the genotype-phenotype association in four Chinese families with OI.

Methods: We designed a targeted next generation sequencing panel with known fourteen OI-related genes. We applied the approach to detect pathogenic mutations in OI patients and confirmed the mutations with Sanger sequencing and cosegregation analysis. Clinical fractures, bone mineral density (BMD) and the other clinical manifestations were evaluated. We also observed the effects of bisphosphonates in OI patients with WNT1 mutations.

Results: Four compound heterozygous mutations (c.110T>C; c.505 G>T; c. 385G>A; c.506 G>A) in WNT1 were detected in three unrelated families. These four mutations had not been reported yet. A recurrent homozygous mutation (c.506dupG) was identified in the other two families. These patients had moderate to severe OI, white to blue sclera, absence of dentinogenesis imperfecta and no brain malformation. We did not observe clear genotype-phenotype correlation in WNT1 mutated OI patients. Though bisphosphonates increased BMD in WNT1 related OI patients, height did not increase and fracture continued.

Conclusions: We reported four novel heterozygous variants and confirmed a previous reported WNT1 mutation in four Chinese families with a clinical diagnosis of OI. Our study expanded OI spectrum and confirmed moderate to severe bone fragility induced by WNT1 defects.

Keywords: Next generation sequencing; Osteogenesis imperfecta; WNT1.

MeSH terms

  • Adolescent
  • Child
  • China
  • Female
  • Genotype
  • Humans
  • Male
  • Mutation*
  • Osteogenesis Imperfecta / diagnosis
  • Osteogenesis Imperfecta / genetics*
  • Phenotype
  • Wnt1 Protein / genetics*


  • WNT1 protein, human
  • Wnt1 Protein