Molecular Genetics of Aniridia

Abstract Aniridia is a rare congenital disorder of eye development in which the characteristic feature is hypoplastic or absent iris tissue. Further ocular changes affecting the cornea, intraocular pressure, retina and lens can occur as the patient ages, which can lead to progressive visual loss and other changes such as optic nerve malformations may occur. Most typical aniridia cases are associated with dominantly inherited null mutations or deletions of the PAX6 gene and the missense mutations are usually associated with mild aniridia or other ocular developmental abnormalities such as Peter's anomaly or isolated foveal hypoplasia. Rarely, mutations of other genes such as FOXC1 can underlie aniridia. Clinical and genetic testing of new sporadic cases aids diagnosis and is crucial to exclude a risk of the malignant Wilms’ tumour. A testing strategy in which deletions are first assessed, followed by sequencing, is suggested as most efficient, particularly for ensuring that a risk of Wilms’ tumour is identified early to ensure screening for this tumour is not delayed in at‐risk individuals. Familial aniridia is much less likely to be associated with Wilms’ tumour risk but there can be marked phenotypic variability amongst family members. Long‐term care includes screening for and management of eye complications such as glaucoma and surgery for cataract, supportive care for visual impairment and long‐term renal monitoring and therapy for those with WT1 deletions. Key Concepts: Aniridia is a rare, sight‐threatening panocular disorder. The major clinical feature is congenital absence or hypoplasia of the iris; most cases also demonstrate foveal hypoplasia with reduced visual acuity and nystagmus. Progressive sight‐threatening complications occur later and include keratopathy, cataract and glaucoma. The PAX6 gene at 11p13 encodes a highly conserved transcription factor crucial for early ocular development. In the vast majority of cases, aniridia is caused by loss of function of one copy (haploinsufficiency) of the PAX6 gene by intragenic mutation or chromosomal rearrangement. Missense mutations in the PAX6 paired domain often cause other ocular phenotypes such as Peter's anomaly and foveal hypoplasia but may also cause a mild aniridia phenotype. Familial aniridia cases show autosomal‐dominant inheritance with high penetrance but considerable phenotypic heterogeneity. Newborns with sporadic aniridia are at high risk of the malignant Wilms’ tumour if they have a deletion encompassing PAX6 and the nearby WT1 gene. Such deletions may manifest as WAGR syndrome. A genetic testing strategy that assesses for deletions first and then sequencing will ensure the early identification of a high risk for Wilms’ tumour and directs sequencing to those more likely to have intragenic mutations.