Departamento de Genética, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; Área de Genética & Genómica, Instituto de Investigación Sanitaria - Fundación Jiménez Díaz - Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain; Centro de Investigación en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
Departamento de Genética, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; Área de Genética & Genómica, Instituto de Investigación Sanitaria - Fundación Jiménez Díaz - Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
Arch Soc Esp Oftalmol (Engl Ed). 2021 Nov;96 Suppl 1:4-14. doi: 10.1016/j.oftale.2021.02.002. Epub 2021 Oct 22.
Aniridia is a panocular disease characterized by iris hypoplasia, accompanied by other ocular manifestations, with a high clinical variability and overlapping with different abnormalities of the anterior and posterior segment. This review focuses on the genetic features of this autosomal dominant pathology, which is caused by the haploinsufficiency of the PAX6 gene. Mutations causing premature stop codons are the most frequent among the wider mutational spectrum of PAX6, with more than 600 different mutations identified so far. Recent advances in next-generation sequencing (NGS) have increased the diagnostic yield in aniridia and contributed to elucidate new etiopathogenic mechanisms leading to PAX6 haploinsufficiency. Here, we also update good practices and recommendations to improve genetic testing and clinical management of aniridia using more cost-effective NGS analysis. Those new approaches also allow studying simultaneously both structural variants and point-mutations in PAX6 as well as other genes for differential diagnosis, simultaneously. Some patients with atypical phenotypes might present mutations in FOXC1 and PITX2, both genes causing a wide spectrum of anterior segment dysgenesis, or in ITPR1, which is responsible for a distinctive form of circumpupillary iris aplasia present in Gillespie syndrome, or other mutations in minor genes. Since aniridia can also associate extraocular anomalies, as it occurs in carriers of PAX6 and WT1 microdeletions leading to WAGR syndrome, genetic studies are crucial to assure a correct diagnosis and clinical management, besides allowing prenatal and preimplantational genetic testing in families.
无虹膜症是一种全眼球疾病，其特征为虹膜发育不全，伴有其他眼部表现，具有较高的临床变异性，并与前节和后节的不同异常重叠。本综述重点介绍这种常染色体显性病理的遗传特征，该病理由 PAX6 基因的单倍不足引起。在 PAX6 更广泛的突变谱中，引起过早终止密码子的突变是最常见的，迄今为止已经确定了超过 600 种不同的突变。新一代测序（NGS）的最新进展提高了无虹膜症的诊断产量，并有助于阐明导致 PAX6 单倍不足的新发病机制。在这里，我们还更新了使用更具成本效益的 NGS 分析来改进无虹膜症遗传检测和临床管理的良好实践和建议。这些新方法还允许同时研究 PAX6 及其他基因的结构变异和点突变，以进行鉴别诊断。一些具有非典型表型的患者可能会出现 FOXC1 和 PITX2 的突变，这两种基因都会导致广泛的前节发育不良，或者 ITPR1 的突变，这种突变会导致 Gillespie 综合征中特有的瞳孔周围虹膜缺失，或者其他小基因的突变。由于无虹膜症还可能与眼外异常相关，如 PAX6 和 WT1 微缺失导致的 WAGR 综合征的携带者，因此遗传研究对于确保正确的诊断和临床管理至关重要，同时还允许在家庭中进行产前和植入前的遗传检测。
