Whole-Exome Sequencing Identifies Novel Compound Heterozygous ZNF469 Mutations in Two Siblings with Mild Brittle Cornea Syndrome
Tim Rolvien, Uwe Kornak, Stephan J. Linke, Michael Amling, Ralf Oheim
Abstract
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.