VEGFA variants as prognostic markers for the retinopathy in pseudoxanthoma elasticum

Abstract

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.

Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis

“…Unfortunately, for this approach large groups are needed to obtain statistically valid results, especially when using whole exome sequencing ( Zarbock et al, 2009 ). In PXE, single-marker tests were used to identify single nucleotide polymorphisms (SNPs) in the VEGFA gene as modifiers of the severity of the ocular phenotype, using a candidate gene approach ( Boraldi et al, 2014 ; De Vilder et al, 2020 ). Further, the allelic variant epsilon2/epsilon3 of the APOE gene was suggested as a modifying factor for the cardiovascular PXE phenotype with a seemingly protective effect in older age ( Clarke et al, 2013 ).…”

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

“…The identification and contribution of peripheral tissues to calcification regulation remains unresolved. Plasma PPi levels fail to explain the wide range of calcification severity in humans [ 17 ] and mice [ 111 ] ( Cf Figure 1 ) and the clinical relevance of potential modifier genes [ 109 , 110 , 147 , 150 , 154 , 155 , 156 ] is still unknown. Finally, what is (if any) the role of inflammation in the progression of PXE [ 159 ]?…”

“…Pancreatic islet hyperplasia was observed as well as fibro-osseous lesions in several bones. More interesting is that these strains of mice carry the exact same Abcc6 gene mutation and have similar plasma PPi levels ( Figure 2 ), which clearly underlie the possible role of other factors such as the environment [ 19 ] and/or modifier genes in the development of ectopic calcification [ 109 , 110 ].…”

“…However, a very recent clinical study performed with 289 PXE patients found that mixed genotype led to less severe arterial calcification and ocular manifestations than patients with two truncating ABCC6 variants and suggested that environmental or modifier genes could also contribute to the still unexplained phenotypic variability in PXE [ 153 ]. The presence of modifier genes modulating calcification in PXE has been investigated in human and mice but their predictive values for clinical applications are not clear [ 109 , 110 , 147 , 150 , 154 , 155 , 156 ]. Moreover, PXE is a slow and chronic disease with stepwise progression of the phenotype occurring over a period of time measured in years, if not decades [ 157 ].…”

From membrane to mineralization: the curious case of the ABCC6 transporter

“…Zarbock et al . associated five VEGFA polymorphisms with a more severe ocular phenotype; a recent independent follow‐up study could confirm this association for three of these polymorphisms (rs13207351, rs1413711, and rs833061) which opens the avenue for prospective evaluations of these variants as prognostic markers for the development and natural history of a PXE‐associated retinopathy [115,116].…”