Abstract：
Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled-4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock-down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway\'s key protein frizzled-4, are known to cause FEVR. However, it is not clear what effect different FZD4 variants have, and whether extraocular features should be expected in those with biallelic pathogenic FZD4 variants. Biallelic FZD4 variants were found in a young boy with isolated, severe FEVR. His parents were heterozygous for one variant each and reported normal vision. In-vitro studies of the two variants, demonstrated that it was the combination of the two which led to severe inhibition of the Norrin/Frizzled-4 pathway. Our observations demonstrate that biallelic FZD4-variants are associated with a severe form of FEVR, which does not necessarily include extraocular features. In addition, variants causing severe FEVR in combination, may have no or minimal effect in heterozygous parents as non-penetrance is also a major feature in dominant FZD4-FEVR disease. This underscores the importance of genetic testing of individuals and families with FEVR.
摘要：
家族性渗出性玻璃体视网膜病变（FEVR）与Norrin/Frizzled-4信号通路的破坏有关，在视网膜血管生成中起重要作用。该途径中蛋白质的严重或完全敲除也会导致该病症的综合征形式。FZD4基因中的杂合和双等位基因致病变体，编码该途径的关键蛋白frizzled-4，已知会导致FEVR。然而,目前还不清楚不同的FZD4变体有什么效果，以及具有双等位基因致病性FZD4变异体的患者是否应具有眼外特征。在一个孤立的小男孩中发现了双等位基因FZD4变体，严重的FEVR。他的父母是杂合的，每个变种都有一个变种，并报告视力正常。这两种变体的体外研究，证明是两者的结合导致了对Norrin/Frizzled-4途径的严重抑制。我们的观察结果表明，双等位基因FZD4变体与严重形式的FEVR有关，这不一定包括眼外特征。此外,导致严重FEVR的变异组合，由于非外显率也是显性FZD4-FEVR疾病的主要特征，因此在杂合亲本中可能没有或影响最小。这强调了使用FEVR对个人和家庭进行基因检测的重要性。
