Wawrzynski James, Patel Aara, Badran Abdul, Dowell Isaac, Henderson Robert, Sowden Jane C
UCL Great Ormond Street Institute of Child Health, National Institute for Health and Care Research, University College London, London, United Kingdom.
Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom.
Front Genet. 2022 May 16;13:884722. doi: 10.3389/fgene.2022.884722. eCollection 2022.
The inner retina is supplied by three intraretinal capillary plexi whereas the outer retina is supplied by the choroidal circulation: NDP is essential for normal intraretinal vascularisation. Pathogenic variants in NDP (Xp11.3) may result in either a severe retinal phenotype associated with hearing loss (Norrie Disease) or a moderate retinal phenotype (Familial Exudative Vitreoretinopathy, FEVR). However, little is known about whether the nature or location of the NDP variant is predictive of severity. In this systematic review we summarise all reported NDP variants and draw conclusions about whether the nature of the NDP variant is predictive of the severity of the resulting ocular pathology and associated hearing loss and intellectual disability. 201 different variants in the NDP gene have been reported as disease-causing. The pathological phenotype that may result from a disease-causing NDP variant is quite diverse but generally comprises a consistent cluster of features (retinal hypovascularisation, exudation, persistent foetal vasculature, tractional/exudative retinal detachment, intellectual disability and hearing loss) that vary predictably with severity. Previous reviews have found no clear pattern in the nature of NDP mutations that cause either FEVR or Norrie disease, with the exception that mutations affecting cysteine residues have been associated with Norrie Disease and that visual loss amongst patients with Norrie disease tends to be more severe if the NDP mutation results in an early termination of translation as opposed to a missense related amino acid change. A key limitation of previous reviews has been variability in the case definition of Norrie disease and FEVR amongst authors. We thus reclassified patients into two groups based only on the severity of their retinal disease. Of the reported pathogenic variants that have been described in more than one patient, we found that any given variant caused an equivalent severity of retinopathy each time it was reported with very few exceptions. We therefore conclude that specific NDP mutations generally result in a consistent retinal phenotype each time they arise. Reports by different authors of the same variant causing either FEVR or Norrie disease conflict primarily due to variability in the authors' respective case definitions rather than true differences in disease severity.
视网膜内层由三个视网膜内毛细血管丛供血，而视网膜外层由脉络膜循环供血：NDP 对于正常的视网膜内血管形成至关重要。NDP（Xp11.3）的致病变异可能导致与听力丧失相关的严重视网膜表型（诺里病）或中度视网膜表型（家族性渗出性玻璃体视网膜病变，FEVR）。然而，关于 NDP 变异的性质或位置是否可预测严重程度，人们知之甚少。在本系统评价中，我们总结了所有已报道的 NDP 变异，并得出关于 NDP 变异的性质是否可预测所导致的眼部病理严重程度以及相关听力丧失和智力残疾的结论。已报道 NDP 基因中有 201 种不同的变异为致病变异。致病的 NDP 变异可能导致的病理表型相当多样，但通常包括一组一致的特征（视网膜血管减少、渗出、永存原始玻璃体、牵拉性/渗出性视网膜脱离、智力残疾和听力丧失），这些特征会随严重程度而有可预测的变化。先前的综述发现，导致 FEVR 或诺里病的 NDP 突变的性质没有明确模式，唯一的例外是影响半胱氨酸残基的突变与诺里病相关，并且如果 NDP 突变导致翻译提前终止而非错义相关的氨基酸变化，诺里病患者的视力丧失往往更严重。先前综述的一个关键局限性是作者之间对诺里病和 FEVR 的病例定义存在差异。因此，我们仅根据患者视网膜疾病的严重程度将其重新分为两组。在已报道的多个患者中描述过的致病变异中，我们发现任何给定的变异每次被报道时都会导致同等严重程度的视网膜病变，只有极少数例外。因此，我们得出结论，特定的 NDP 突变每次出现时通常会导致一致的视网膜表型。不同作者关于同一变异导致 FEVR 或诺里病的报道相互矛盾，主要是由于作者各自病例定义的差异，而非疾病严重程度的真正差异。
