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Association of variants in the VEGFA (Vascular Endothelial Growth Factor) gene with severe retinopathy in pseudoxanthoma elasticum: implications for molecular screening, counseling and management
Book Contribution - Book Abstract Conference Contribution
AIMS: one of the most incapacitating symptoms of pseudoxanthoma elasticum (PXE) - a connective tissue disease with remarkable variability in clinical severity - is subretinal (choroidal) neovascularization and subsequent blindness, due to increased VEGFA activity. We aim to validate single nucleotide polymorphisms (SNPs) in the VEGFA gene as prognostic biomarkers for the PXE retinopathy which could be used for ocular risk stratification and hence counseling and follow-up of PXE families.METHODS: the VEGFA coding and non-coding (intronic and promotor) regions were Sanger sequenced in 65 molecularly confirmed PXE patients with a mild, respectively severe retinopathy. The latter was defined as unilateral best corrected visual acuity (BCVA) < 5/10 (with an impact on quality of life) and/or the need for anti-angiogenesis treatment with multiple anti-VEGF injections. Associations of VEGFA SNPs with disease severity and anti-VEGF therapeutic outcome were evaluated.RESULTS: a significant association of 5 VEGFA SNPs with severe retinopathy - but not with therapeutic outcome - was found, 4 of which had been previously suggested to be involved in the PXE ocular phenotype. Importantly, in several patients severe eye disease was characterized by an increased need for anti-VEGF therapy due to neovascularization, even with (near) normal BCVA. Hence, carriers of these SNPs have a more active eye disease but will not necessarily go blind if followed and treated sufficiently strict.CONCLUSIONS: the association of 4 VEGFA SNPs with a severe PXE retinopathy could be validated in an independent patient cohort, providing reliable data to stratify PXE patients for the ophthalmological complications and individualize counseling and management in the high-risk group. Prospective evaluation is ongoing to evaluate the outcome of such a personalized regime. Apart from the benefits for patient management, the need for validated prognostic biomarkers for the different phenotypic features of PXE is also essential for the design and interpretation of clinical trials. This is a pressing need, as novel pathophysiological and molecular insights in PXE have recently paved the way for human trials with allele-specific treatment using 4-phenylbutyrate or anti-mineralization therapy using bisphosphonates. Based on our results, genotyping of these VEGFA genetic biomarkers is now done in the design of such trials in PXE patients.
Book: Belgian Society of Human Genetics (BeSHG) and the Nederlandse Vereniging voor Humane Genetica (NVHG), 1st Joint meeting, Abstract book
Number of pages: 1