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.

中文翻译：

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VEGFA变异体是假性假性黄瘤中视网膜病变的预后标志物。

弹性假黄瘤（PXE）是一种罕见的常染色体隐性异位矿化性疾病，其特征是皮肤，眼睛和心血管症状。最破坏性的眼部并发症是脉络膜新血管形成，其被认为是由血管内皮生长因子（VEGF）信号介导的，该信号由VEGFA基因编码。由于早期发现和治疗对于保持视力至关重要，因此对处于风险中的患者进行优先级排序至关重要，但由于表型变异性大且缺乏PXE的基因型与表型相关性，因此不可能。这项研究旨在验证先前建议的五种单核苷酸VEGFA的关联独立队列中患有严重PXE视网膜病变的变体（rs13207351，rs833061，rs699947，rs25648和rs1413711）。在100例轻度（56）或重度（44）PXE视网膜病变的PXE患者中进行了直接Sanger测序。严重视网膜病变的纳入标准为单侧最佳矫正视力<5/10和/或需要抗血管生成治疗。我们发现了五个变体中的三个的显着关联，而边界线对一个变体的意义缺失。这些数据进一步表明VEGFA基因是PXE视网膜病的修饰基因。因此，我们提供了必要的证据，以在眼部风险分层和患者个体化随访中实施这些变异。