VEGFA variants as prognostic markers for the retinopathy in pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive ectopic mineralization disorder, characterized by skin, eye and cardiovascular symptoms. The most devastating ocular complication is choroidal neovascularization, which is thought to be mediated by vascular endothelial growth factor (VEGF) signaling, a molecule encoded by the VEGFA gene. As early detection and treatment is essential to preserve vision, prioritization of patients at risk is crucial, but impossible because of wide phenotypic variability and a lack of genotype-phenotype correlations for PXE. This study aimed to validate the previously suggested association of five single nucleotide VEGFA variants (rs13207351, rs833061, rs699947, rs25648 and rs1413711) with a severe PXE retinopathy in an independent cohort. Direct Sanger sequencing was performed in 100 PXE patients, with a mild (56) or severe (44) PXE retinopathy. The inclusion criteria for severe retinopathy were a unilateral best-corrected visual acuity of <5/10 and/or the need for anti-angiogenic treatment. We found a significant association of three of five variants and borderline missed significance for one. These data further suggest the VEGFA gene to be a modifier gene for the PXE retinopathy. Hereby, we provide the necessary evidence to implement these variants in ocular risk stratification and individualized patient follow-up.