Abstract
Purpose :
To investigate the ophthalmic manifestations and genetic basis of a rare, atypical phenotype of corneal ectasia associated with posterior lamellar corneal opacification.
Methods :
Slit lamp exam and multi-modal imaging were performed on affected individuals and their unaffected relatives, followed by saliva collection for DNA extraction after informed consent was obtained (UCLA IRB 11-000020). Whole genome comparative genomic hybridization (CGH) was used to screen DCN, KERA, LUM, and EPYC genes for copy number variants (CNV) associated with posterior amorphous corneal dystrophy (PACD). PCR amplification and Sanger sequencing were used to screen ZNF469 and PRDM5 coding regions, associated with brittle cornea syndrome (BCS), as well as ZEB1 coding, OVOL2 promoter, and GRHL2 promoter, exon 1, and intron 1 regions, associated with posterior polymorphous corneal dystrophy (PPCD). Rare variants were defined as having minor allele frequencies <0.01.
Results :
Three unrelated individuals diagnosed with PACD had bilateral corneal steepening, stromal thinning and posterior lamellar corneal opacification. Corneal topography showed conical corneal deformation. Anterior segment optical coherence tomography showed posterior stromal hyperreflectivity. CGH did not detect any clinically significant CNV. Among affected individuals, genetic screening identified 4 rare, heterozygous mutations, of which 2 (ZNF469 (c.8847C>G (His2949Glu) and ZEB1 c.2203C>G (Leu735Val)) were missense and 2 (ZNF469 c.8325C>T (Pro2775=) and PRDM5 c.1851C>T (Leu617=)) were synonymous. Both missense mutations were detected in an unaffected parent.
Conclusions :
While posterior lamellar corneal opacification is consistent with PACD, corneal steepening is not, but may be seen in BCS or PPCD. The absence of clinically significant CNV in DCN, KERA, LUM, and EPYC excludes PACD. Given that the identified rare ZNF469 and ZEB1 variants do not segregate with the affected status, these variants are likely not pathogenic, which combined with the lack of rare missense variants in PRDM5, GRHL2, and OVOL2 exclude both BCS and PPCD. Preliminary genetic analysis thus suggests an uncharacterized phenotype of corneal ectasia with abnormalities of corneal curvature, thickness and clarity. This also illustrates the importance of molecular genetics in diagnosis. More cases and studies are required to further characterize this rare phenotype.
This is a 2020 ARVO Annual Meeting abstract.