Punctiform and Polychromatic Pre-Descemet Corneal Dystrophy: Clinical Evaluation and Identification of the Genetic Basis

Abstract Purpose To report the clinical features and genetic basis of three previously unreported families with punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD). Design Case series. Methods Full ophthalmic assessment was performed for members of three unreported families with PPPCD. Structural and biomechanical alterations of the cornea were screened. Whole-exome-sequencing (WES) was performed on the first family. Novel or rare variants that segregated with the affected status were screened for in the other two families with Sanger sequencing. Identified variants that segregated with the affected status in all families were characterized using in silico prediction tools and/or in vitro splice assays. Additionally, two previously reported PPPCD families were screened for variants identified in the three unreported PPPCD families. Results Twelve of 21 examined members of the three unreported families were diagnosed with PPPCD. The only refractive, topographic or biomechanical abnormality associated with PPPCD was a significantly increased corneal stiffness. WES and Sanger sequencing identified two variants that segregated with the affected status in the all three families: a rare intronic PDZD8 c.872+10A>T variant and a novel missense PRDX3 c.568G>C (p.Asp190His) variant. The same PRDX3 variant was identified in the previously reported PPPCD family expressing the common PPPCD phenotype, and is predicted by in silico prediction tools to be damaging to protein function. Conclusions PPPCD is associated with an alteration of corneal biomechanics and a novel missense variant in PRDX3. Screening of additional families will determine whether all families demonstrate a PRDX3 variant, or whether locus heterogeneity may exist for PPPCD.