More than meets the eye: Expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome

Abstract

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum.It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype-and phenotype-oriented literature overview of all (n = 85) reported patients with ZNF469 (n = 53) and PRDM5 (n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition.

NRF2 Shortage in Human Skin Fibroblasts Dysregulates Matrisome Gene Expression and Affects Collagen Fibrillogenesis

“…To assess the possible pathophysiological significance of our data, we analyzed expression of collagen I and V genes in dermal fibroblasts of two BCS patients (P1 and P2) carrying mutations in ZNF469 that both result in a premature termination codon (PTC) (Figure 5c) (Dhooge et al, 2021). No change in ZNF469 expression level was observed in BCS fibroblasts (Figure 5d) indicating that these PTC-containing mRNAs escape non-sense-mediated RNA decay.…”

The Ehlers–Danlos Syndromes against the Backdrop of Inborn Errors of Metabolism

“…Rupture of the eye globes, either spontaneous or after minor trauma, due to extreme thinning of the cornea is the cardinal feature of brittle cornea syndrome (BCS) and perhaps one of the most debilitating complications within the EDS spectrum [ 12 , 27 ]. It frequently occurs at a young age; however, several adults without ocular rupture have been described.…”

“…Hearing loss is a key finding in heritable connective tissue disorders, such as osteogenesis imperfecta and Stickler syndrome but is also present in the majority of individuals with kEDS- FKBP14 or mcEDS and a third of the individuals with BCS [ 7 , 12 , 27 ]. Finally, cryptorchidism is present in the large majority of mcEDS- CHST14 individuals and should raise suspicion of mcEDS in a neonate with signs of connective tissue fragility and contractures [ 7 ].…”

A mouse model of brittle cornea syndrome caused by mutation in Zfp469

“…The role played by ZNF469 in the healthy cornea and in BCS is less clear as the function of the very large protein encoded by this gene is poorly characterised. Since mutations in ZNF469 were first reported to cause BCS (Abu et al, 2008), 30 pathogenic compound heterozygous or homozygous mutations have been identified in the single coding exon of ZNF469 spanning 13 kilobases on chromosome 16q24.2 (Abu et al, 2008;Al-Owain et al, 2012;Christensen et al, 2010;Dhooge et al, 2021;Khan et al, 2012;Khan et al, 2010;Menzel-Severing et al, 2019;Micheal et al, 2019;Ramappa et al, 2014;Rolvien et al, 2020;Skalicka et al, 2020). The majority of these mutations result in premature stop codons that are hypothesised to lead to production of truncated and non-functional protein and are thus considered as loss of function (LOF) mutations.…”