Identification of Six Novel Mutations inZEB1and Description of the Associated Phenotypes in Patients with Posterior Polymorphous Corneal Dystrophy 3

Abstract

SummaryPosterior polymorphous corneal dystrophy 3 (PPCD3) is a rare autosomal dominant disorder caused by mutations in ZEB1. To date all identified disease-causing variants were unique to the studied families, except for c. included bilateral congenital corneal opacity in one proband, development of opacity before the age of 2 years in another individual and bilateral iris flocculi in yet another subject. The majority of eyes examined by corneal topography (10 out of 16) had an abnormally steep cornea (flat keratometry 46.5-52.7 diopters, steep keratometry 48.1-54.0 diopters). One proband underwent surgery for cryptorchidism. Our study further demonstrates that PPCD3 can present as corneal edema in early childhood, and that an abnormally steep keratometry is a common feature of this condition. As cryptorchidism has been previously observed in two other PPCD3 cases, its association with the disease warrants further investigation.

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

“…[9][10][11][12][14][15][16][17] In this study, we show that heterozygous deletions of the ZEB1 gene cause PPCD3, verifying that haploinsufficiency of ZEB1 is the mechanism of disease.…”

“…1,16 For inclusion in this analysis, the presence of ZEB1 coding and/or splice-site mutations by direct sequencing had previously been excluded. 11,16,17 All probands identified to be positive for ZEB1 locus deletions in the current study were also negative for mutations in COL8A2, either by Sanger sequencing or by whole-exome sequencing (WES) (unpublished data). 11 …”

“…[2][3][4] The proportion of PPCD cases attributed to mutations in ZEB1 has been reported to be between 9 and 34%. [9][10][11][12][14][15][16][17] Our results demonstrate that the number of cases with PPCD3 is underestimated, because standard screening techniques do not detect deletions spanning such large regions. We have therefore developed an assay for the rapid and reliable detection of ZEB1 deletions using qRT-PCR.…”

“…20,24 PPCD often presents in small nuclear families or as an isolated case such that linkage to a specific genomic region is not conclusive, or is confounded by incomplete penetrance in some cases, so a substantial proportion of patients currently lack a molecular diagnosis. [9][10][11][12][14][15][16][17] In this study we demonstrate that, in some of these cases, PPCD can be attributed to heterozygous deletions at the ZEB1 locus, providing insights into the molecular diagnosis of previously unexplained PPCD cases and verifying haploinsufficiency as the mechanism of disease for PPCD3.…”

“…[9][10][11][12][13][14][15][16][17] There are regional variations in the contribution of these PPCD subtypes, and the proportion attributed to ZEB1 mutations (PPCD3) has been reported to be 9% in New Zealand, 20% in the Czech Republic, 30% in the United Kingdom and Canada, and 34% in the United States. [9][10][11][12][13][14][15][16][17] In contrast to other PPCD subtypes, PPCD3 is often associated with corneal steepening. 16,18 Systemic features such as inguinal hernias have also been described.…”