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.

Keywords: aniridia; PAX6; eye; iris; foveal hypoplasia; WAGR syndrome; anterior segment dysgenesis; Wilms' tumour

Figure 1.

Partial absence of iris tissue with distorted enlarged pupil. Scar tissue in lens capsule (capsular opacification) from previous cataract surgery.

Figure 2.

Complete absence of iris tissue and peripheral corneal changes causing opacification of the corneal edge. Linear cataracts are seen in a radial pattern through the central clear cornea.

Figure 3.

Photograph of marked aniridic corneal changes showing dense central scarring and new blood vessels growing in from the periphery.

Figure 4.

End‐stage aniridic eye following multiple surgeries: corneal changes with total opacity and vessel ingrowth and a shrunken (phthisical) eye.

Figure 5.

Diagram to show known location of known missense mutatons of PAX6.

Figure 6.

Strategy for genetic testing after clinical diagnosis of aniridia.

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Further Reading

Chang TC, Summers CG, Schimmenti LA and Grajewski AL (2012) Axenfeld‐reiger syndrome: new perspectives. British Journal of Ophthalmology 96: 318–322.

Clericuzio C, Hingorani M, Crolla J and van Heyningen V (2011) WAGR syndrome. EuroGenTest eurogentest.org; http://www.nature.com/ejhg/journal/v19/n4/full/ejhg2010220a.html

Hingorani M and Moore T (2008). Aniridia. In GeneReviews: http://www.ncbi.nlm.nih.gov/books/NBK1360/

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Wu HY, Snyder HM and D'Angion DJ (2005) Wilms tumour management. Current Opinion in Urology 15: 273–275.

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Hingorani, Melanie(Sep 2013) Molecular Genetics of Aniridia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024300]