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

Tim Rolvien,Stephan J Linke,Ralf Oheim,Michael Amling,Uwe Kornak

doi:10.1007/s00223-020-00721-3

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.

Highlights

Connective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity
After all known OI genes were excluded by gene panel analysis, whole-exome sequencing of the index patient (II.1) and both parents revealed two heterozygous variants c.10664delC p.(Pro3556Glnfs*136) and c.10240delA p.(Arg3414Glyfs*59) in the ZNF469 gene (Fig. 1a, b)
We present two novel compound heterozygous ZNF469 mutations causing a mild form of brittle cornea syndrome (BCS) that shows clinical resemblance with the extraskeletal manifestations of osteogenesis imperfecta (OI) type I

Summary

Introduction

Connective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity. OI is a well-described genetic skeletal disorder defined by increased bone fragility, which is most commonly caused by heterozygous mutations in two genes encoding type 1 collagen (COL1A1/COL1A2), many other forms and gene mutations have been identified [1]. A number of extraskeletal symptoms including blue sclerae, joint hypermobility and hearing loss have been described [1]. Joint hypermobility is primarily a typical sign of EDS, a genetic connective tissue disorder caused by specific collagen mutations (type I, III or V) or other mutations in genes involved in collagen production or processing [2, 3]. Mutations in ZNF469 cause brittle cornea syndrome (BCS) [5, 6], a multisystem connective tissue disorder primarily associated with corneal thinning and blue sclerae and joint hypermobility [7].

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Conclusion