PAX6 gene


Gene (OMIM No.)
Function of gene/protein
  • Protein: Paired box 6
  • Regulates other genes by binding to specific DNA regions (transcription factor)
  • During embryonic development, PAX6 activates genes involved in eye, central nervous system and pancreas development
  • Also important for maintaining normal function of certain cells after birth, particularly in the eye
Clinical phenotype
(OMIM phenotype no.)
Ocular featuresAniridia and cataract with late onset corneal dystrophy:
  • Most common phenotype with significant intra- and interfamilial variability in clinical presentation and severity
  • Iris hypoplasia
  • Nystagmus
  • Cataract
  • Secondary glaucoma
  • Aniridia-related keratopathy
  • Foveal hypoplasia
  • Optic nerve hypoplasia
  • May present with microphthalmia, anophthalmia, coloboma (MAC) spectrum
Other reported phenotypes:
Systemic features
  • WAGR syndrome (with concurrent WT1 deletion)
  • Brain abnormalities (structural abnormalities of the pituitary and pineal glands, hypoplastic or absent anterior commissure, hypoplastic corpus callosum, partial or complete agenesis of the septum pellucidum)
  • Neurodevelopmental abnormalities
  • Sleep disturbances/narcolepsy (due to pineal gland abnormalities)
  • Olfactory dysfunction
  • Obesity
  • Diabetes mellitus
Key investigations
  • USS biomicroscopy or anterior segment OCT to assess for anterior segment abnormalities if corneal clouding is present
  • B-scan USS to measure axial length to document microphthalmia if present
  • OCT to detect for foveal hypoplasia
  • Electrophysiology to establish visual potential
  • Systemic assessment with a paediatrician and other relevant specialists
  • MRI brain and orbit
  • Regular renal USS monitoring in aniridia to detect for Wilms tumour until absence of WT1 deletion is confirmed via genetic testing
Molecular diagnosis
  • Cytogenetic testing to exclude PAX6 and WT1 deletion (WAGR syndrome)
  • Direct sequencing of PAX6 once WAGR syndrome is excluded
  • Targeted gene panels for those presenting with non-aniridia phenotypes (MAC, ASD, congenital cataract, isolated foveal hypoplasia)
  • Whole genome sequencing
Therapies under research
Further information

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Additional information

Majority of PAX6 variants disrupt protein transcription or translation leading to minimal or absent protein production (PAX6 haploinsufficiency), which usually result in the pan-ocular disorder aniridia.[1] Missense variants (mostly found in exons 5 and 6) tend to be associated with non-aniridia phenotypes such as microphthalmia, coloboma, foveal hypoplasia with or without anterior segment dysgenesis and/or cataract.[2-6] Due to the high phenotypic variability among PAX6 mutations, it is often challenging to establish a clear genotype-phenotype correlation.[7]

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Clinical images

A series of images showing the eyes of different patients with PAX6 mutations. The iris of one patient is poorly formed with clouding of the cornea, and incomplete development of the fovea. The overall size of the eye is smaller than usual in another patient. The third patient has a fully formed iris but the foveal is not fully developed.
Range of PAX6 phenotypes. Typical PAX-related aniridia with iris hypoplasia with corneal opacity and vascularisation (A). Corresponding fundal image shows absent foveal reflex (B) and OCT shows foveal hypoplasia (C). Left eye of a patient with PAX6-related microphthalmia, microcornea and corneal neovascularisation (D). A patient with dominant nystagmus with no iris hypoplasia (E) and presence of foveal hypoplasia on OCT (F).

Adapted from: Lima Cunha D, Arno G, Corton M, Moosajee M. The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye. Genes. 2019; 10(12):1050.


  1.  Lima Cunha D, Arno G, Corton M, Moosajee M. The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye. Genes (Basel). 2019;10(12):1050
  2.  Azuma N, Yamaguchi Y, Handa H, Hayakawa M, Kanai A, Yamada M. Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies. Am J Hum Genet. 1999 Sep;65(3):656-63
  3.  Thomas S, Thomas MG, Andrews C, et al. Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation. Eur J Hum Genet. 2014;22(3):344-349
  4.  Lima Cunha D, Owen N, Tailor V, Corton M, Theodorou M, Moosajee M. PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism [published online ahead of print, 2020 Oct 6]. Eur J Hum Genet. 2020;10.1038/s41431-020-00737-1
  5.  Hingorani M, Williamson KA, Moore AT, van Heyningen V. Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations. Invest Ophthalmol Vis Sci. 2009;50(6):2581-2590
  6.  Tzoulaki I, White IM, Hanson IM. PAX6 mutations: genotype-phenotype correlations. BMC Genet. 2005;6:27
  7.  Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; May 20, 2003
  8.  Barros-Nunez, P., Medina, C., Mendoza, R., Sanchez-Corona, J., Garcia-Cruz, D. Unexpected familial recurrence of iris coloboma: a delayed mutation mechanism? Clin. Genet. 1995;48: 160-161
  9.  Birkebaek, N. H., Patel, L., Wright, N. B., Grigg, J. R., Sinha, S., Hall, C. M., Price, D. A., Lloyd, I. C., Clayton, P. E. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J. Clin. Endocr. Metab. 2003;88: 5281-5286
  10.  Cheong, S.-S., Hentschel, L., Davidson, A. E., Gerrelli, D., Davie, R., Rizzo, R., Pontikos, N., Plagnol, V., Moore, A. T., Sowden, J. C., Michaelides, M., Snead, M., Tuft, S. J., Hardcastle, A. J. Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis. Am. J. Hum. Genet. 2016; 99: 1338-1352
  11.  Mirzayans, F., Pearce, W. G., MacDonald, I. M., Walter, M. A. Mutation of the PAX6 gene in patients with autosomal dominant keratitis. Am. J. Hum. Genet. 1995;57: 539-548
  12.  Shaw, M. W., Falls, H. F., Neel, J. V. Congenital aniridia. Am. J. Hum. Genet. 1960;12: 389-415
  13.  Sisodiya, S. M., Free, S. L., Williamson, K. A., Mitchell, T. N., Willis, C., Stevens, J. M., Kendall, B. E., Shorvon, S. D., Hanson, I. M., Moore, A. T., van Heyningen, V. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet. 2001;28(3): 214-216
  14.  Azuma N, Yamaguchi Y, Handa H, et al. Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am J Hum Genet. 2003;72(6):1565-1570
  15.  Hanish AE, Butman JA, Thomas F, Yao J, Han JC. Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency. J Sleep Res. 2016;25(1):16-22

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Updated on November 30, 2020
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