PDF(Pubmed)
Abstract：
Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6-related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia. Therefore, the clinical recognition and differential genetic diagnosis of PAX6-related aniridia has been revealed to be much more challenging than initially thought, and still remains under-investigated. Here, we update specific clinical features of aniridia, with emphasis on their genotype correlations, as well as provide new knowledge regarding the PAX6 gene and its mutational spectrum, and highlight the beneficial utility of clinically implementing targeted Next-Generation Sequencing combined with Whole-Genome Sequencing to increase the genetic diagnostic yield of aniridia. We also present new molecular mechanisms underlying aniridia and aniridia-like phenotypes. Finally, we discuss the appropriate medical and surgical management of aniridic eyes, as well as innovative therapeutic options. Altogether, these combined clinical-genetic approaches will help to accelerate time to diagnosis, provide better determination of the disease prognosis and management, and confirm eligibility for future clinical trials or genetic-specific therapies.
摘要：
先天性PAX6-无虹膜,最初的特点是没有虹膜，已逐渐证明与其他发育性眼部异常和系统特征有关，这使先天性无虹膜成为一种复杂的综合征，而不是简单的虹膜疾病。此外，中心凹发育不全现在被认为是比完全虹膜发育不全更常见的特征和主要的视觉预后决定因素。扭转了这种疾病的经典临床表现。相反，虹膜畸形也是由PAX6相关发育基因引起的各种眼前节发育不全的特征，为无虹膜的准确分子诊断增加了一定程度的遗传复杂性。因此,与PAX6相关的无虹膜的临床识别和差异遗传诊断已被发现比最初认为的更具挑战性，但仍未得到充分调查。这里,我们更新了无虹膜的具体临床特征，强调它们的基因型相关性，以及提供有关PAX6基因及其突变谱的新知识，并强调在临床上实施靶向的下一代测序结合全基因组测序以增加无虹膜的遗传诊断产量的有益效用。我们还提出了新的分子机制潜在的无虹膜和无虹膜样表型。最后,我们讨论了适当的医疗和手术管理无虹膜的眼睛，以及创新的治疗选择。总之,这些结合的临床-遗传学方法将有助于加快诊断时间，更好地确定疾病的预后和管理，并确认未来临床试验或基因特异性疗法的资格。
