Whole-Exome Sequencing Identifies Novel Compound Heterozygous ZNF469 Mutations in Two Siblings with Mild Brittle Cornea Syndrome

Calcif Tissue Int. 2020 Sep;107(3):294-299. doi: 10.1007/s00223-020-00721-3. Epub 2020 Jul 15.


Connective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity. We report two sisters with blue sclerae, joint hypermobility and hearing loss. Whole-exome sequencing identified two compound heterozygous ZNF469 loss-of-function mutations due to a frameshift. Since these findings indicate the presence of brittle cornea syndrome (BCS), we performed ocular optical coherence tomography (OCT) and pachymetry, which revealed a moderate decrease in corneal thickness. While only one traumatic fracture was observed in each of the patients, a detailed skeletal assessment indicated no specific patterns of bone mass and microstructure reduction as well as normal bone turnover markers. Taken together, our findings point to a mild form of brittle cornea syndrome with a phenotype compatible with the extraskeletal features of OI but also with EDS.

Keywords: Brittle cornea syndrome; Ehlers-Danlos syndrome; Osteogenesis imperfecta; Whole-exome sequencing; ZNF469.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Exome Sequencing
  • Eye Abnormalities / genetics*
  • Female
  • Humans
  • Joint Instability / congenital*
  • Joint Instability / genetics
  • Middle Aged
  • Mutation
  • Siblings
  • Skin Abnormalities / genetics*
  • Transcription Factors / genetics*


  • Transcription Factors
  • ZNF469 protein, human

Supplementary concepts

  • Brittle cornea syndrome 1