Novel Frameshift Mutation in ZEB1 in a Family with a Severe Form of Posterior Polymorphous Corneal Dystrophy (PPCD)

Purpose: Report of a novel genetic variant in a family with an unusual clinical presentation of posterior polymorphous corneal dystrophy (PPCD). Methods: Documentation of clinical findings of the anterior and posterior segments using slit lamp analysis and imaging tools (Scheimpflug imaging, optical coherence tomography), along with documentation of best spectacle corrected visual acuity (BSCVA; LogMAR). Next-generation sequencing (NGS) of the genes of interest was performed by the IDTxGen® sytem (Inherited Disease Panel v1.0 and sequencing on an Illumina NextSeq® 500) based on DNA extracted from peripheral blood lymphocytes. Data analysis was performed using the SeqNext module of the SEQUENCE Pilot software (version 5.1.0, JSI Medical Systems). A histological examination of four corneas in both patients (father and son) was carried out by hematoxylin-eosin (HE) staining. Results: A novel heterozygous variant in the ZEB1 gene was identified in a 41-year-old man and his 13-year-old son. The 2-bp duplication in exon 8 results in a frameshift and a premature stop codon (p.(Asp883Argfs*39)), predicted to result in nonsense-mediated decay (NMD) and to lead to functional impairment of the ZEB1 protein. The variant was classified as likely pathogenic applying the American College of Medical Genetics and Genomics (ACMG) criteria. The variant is located in the penultimate 3´base pairs of the ZEB1 gene. The C-terminus of the ZEB1 gene encodes the C2H2-type protein domains of the ZEB1 zinc finger transcription factor protein which are relevant in epithelial-mesenchymal transition (EMT) by mediating the transition between cell lineages. The patients presented with an unusual symmetrical crescent-shaped bullous edema with a temporal focus with retrocorneal snail-track-like changes. Histological examination of all hematoxylin-eosin (HE) stained samples revealed a peripheral multilayer of endothelial cells adjacent to the trabecular meshwork (TMW), along with a central reduction of corneal endothelial cells and a pathological thickening of Descemet's membrane of up to 18.7 m. Conclusions: We report a novel variant of dominantly inherited PPCD3. Pathological production of a protein with an effect on the transition between cell lineages could explain the pathogenic epithelial transformation of the corneal endothelium, characterized by snail-track-like retrocorneal changes with a symmetric temporal crescent-shaped corneal edema.