PAX6-Related Aniridia

Clinical characteristics.

PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual.

WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral issues.

Diagnosis/testing.

The diagnosis of PAX6-related aniridia is established in a proband with one of the two following clinical and molecular genetic findings:

• Isolated aniridia (i.e., without systemic involvement) and a heterozygous PAX6 pathogenic variant, ranging in size from a single nucleotide (e.g., those resulting in a nonsense, missense, or splice site variant or single-nucleotide deletion or duplication) to a partial- or whole-gene deletion (or in rare instances deletions telomeric to PAX6 that do not include PAX6); or
• Aniridia and one or more additional findings of WAGR syndrome and a deletion of PAX6 and the upstream adjacent gene, WT1

Management.

Treatment of manifestations:

• Aniridia. Correction of refractive errors, use of tinted or photochromic lenses to reduce light sensitivity, occlusion therapy in childhood for amblyopia, use of low-vision aids. Treatment of severe cataracts requires attention to potential complications caused by poor zonular stability. Glaucoma: Initial treatment is usually topical anti-glaucoma medication; surgery is reserved for eyes that do not respond to medical therapy. Ocular surface disease: medical treatment (lubricants, mucolytics, and punctal occlusion) may help slow the progression of corneal opacification. When corneal opacification causes significant visual reduction, penetrating keratoplasty with limbal stem cell transplantation may be considered; however, this has a high risk of failure and possible lifelong systemic immunosuppression to prevent rejection.
• WAGR syndrome. Wilms tumor, genital anomalies, and developmental delay / intellectual disability are managed as per standard practice.

Surveillance:

• Aniridia. Monitor children younger than age eight years every four to six months for refractive errors and detection and treatment of incipient or actual amblyopia; annual ophthalmology follow up of all individuals to detect issues such as corneal changes, raised intraocular pressure, and cataracts.
• WAGR syndrome. Children with aniridia and a WT1 deletion require renal ultrasound examinations every three months and follow up by a pediatric oncologist until age eight years. Because of the increased risk for renal impairment in WAGR syndrome (especially in those with bilateral Wilms tumor), lifelong evaluation of renal function is recommended. Developmental progress and educational needs require regular monitoring. Behavioral assessment for anxiety, ADHD, and aggressive or self-injurious behavior as needed.

Agents/circumstances to avoid: Intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy; repeated intraocular surgery predisposes to severe aniridic fibrosis syndrome.

Evaluation of relatives at risk: Early clarification of the genetic status of infants who are offspring or sibs of an individual with PAX6-related isolated aniridia (by either an eye examination or molecular genetic testing for the PAX6 variant in the family) is recommended in order to identify those who would benefit from prompt treatment and surveillance of complications of aniridia.

Genetic counseling.

Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner.

• Isolated aniridia. ~70% of individuals have an affected parent; ~30% have a de novo PAX6 pathogenic variant or deletion of a regulatory region controlling PAX6 expression. Each child of an individual with isolated aniridia has a 50% chance of inheriting the causative genetic alteration and developing aniridia. In rare instances of mosaicism for the PAX6 pathogenic variant in the proband, the risk to offspring may be lower.
• WAGR syndrome is associated with contiguous-gene deletions including PAX6 and WT1. If the proband has a de novo contiguous-gene deletion and neither parent has evidence of mosaicism for the deletion, the risk to sibs is no greater than that in the general population.

When the PAX6 genetic alteration in a family is known, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

PAX6-related isolated aniridia should be suspected in probands who have the following clinical and imaging findings of aniridia with no other associated systemic abnormalities.

Clinical findings

• Aniridia. Complete or partial iris hypoplasia best seen on slit lamp examination. Iris translucency or abnormal architecture and pupillary abnormalities may also be seen.
• Reduced visual acuity secondary to:
  • Absence of or reduction in the normal foveal architecture (usually [not always] observed)
  • Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma)
• Early-onset nystagmus (usually apparent by age 6 weeks)
• Microphthalmia and ocular coloboma (iris, chorioretinal, and/or optic disc)

Imaging findings

• Optical coherence tomography (OCT) may be used to document foveal hypoplasia. Although OCT is difficult to perform in the presence of nystagmus, useful images can be obtained with persistence. This should be routinely performed to support a clinical diagnosis, especially where iris defects may be subtle. Anterior segment OCT can also be used to delineate the detailed anatomy of the anterior segment structures, even in those with corneal opacity [Majander et al 2012].
• Ultrasound B-scan should be performed routinely to assess axial length due to the association with microphthalmia.
• High-frequency ultrasound biomicroscopy. In infants with corneal opacity or severe corneal edema resulting from associated congenital glaucoma, high-frequency anterior segment ultrasound examination, usually performed under anesthesia, can demonstrate iris hypoplasia and/or absence [Nischal 2007].
  Note: Iris fluorescein angiography may identify subtle iris hypoplasia but is rarely used clinically.

Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome should be suspected in probands with aniridia and no family history of aniridia who also have at least one of the following findings:

• Wilms tumor (also known as nephroblastoma), a childhood kidney malignancy. Of children with WAGR who develop Wilms tumor, 90% do so by age four years and 98% by age seven years (see Wilms Tumor Predisposition).
• Genitourinary abnormalities. In males: cryptorchidism, hypospadias, ambiguous genitalia; in females: normal external female genitalia, but uterine abnormalities (heart-shaped bicornate uterus) and streak ovaries. In males and females: end-stage kidney disease, ureteric abnormalities, and gonadoblastoma.
• Intellectual disability and/or behavior abnormalities including depression, anxiety, ADHD, obsessive-compulsive disorder, and autism.
• Childhood-onset obesity and pancreatitis

Establishing the Diagnosis

The diagnosis of PAX6-related aniridia is established in a proband with one of the two following clinical and molecular genetic findings (Table 1):

• Isolated aniridia (i.e., without systemic involvement) and a heterozygous PAX6 pathogenic variant, ranging in size from a single nucleotide (e.g., those resulting in a nonsense, missense, or splice site variant or single-nucleotide deletion or duplication) to a partial or whole-gene deletion [Richardson et al 2016]
  Note: Deletions telomeric to PAX6 that do not include PAX6 have been reported.
  • A heterozygous variant in the ultraconserved PAX6 cis-regulatory element (SIMO) that resides 150 kb downstream from PAX6 in intron 9 of ELP4 (NM_001288726.1) causes isolated aniridia [Bhatia et al 2013].
  • MLPA detected a 0.6-Mb deletion downstream of PAX6 on chromosome 11 that encompasses DCDC1, DPH4, IMMP1L, and ELP4 [Wawrocka et al 2012].
  Coverage of these regions on chromosomal or gene-targeted arrays will vary [Blanco-Kelly et al 2017, Franzoni et al 2017].
• Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome and EITHER of the following:
  • A deletion of PAX6 and the upstream adjacent gene, WT1
    Note: Reported deletions include the recurrent 11p13 deletion (see Table 1).
  • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia.
    Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities.

Molecular genetic testing can establish the molecular basis of aniridia, and thus distinguish between isolated aniridia (no increased risk for Wilms tumor) and WAGR (markedly increased risk for Wilms tumor). In the following scenarios molecular genetic testing approaches are based on the individual's age, clinical findings, family history, and testing methods available.

Scenario 3

The proband is either an infant with aniridia and genital anomalies or an older individual with aniridia and intellectual disability and/or Wilms tumor and/or genital anomalies. Perform CMA to identify a contiguous-gene deletion that includes PAX6 and WT1.

Table 1.

Molecular Genetic Testing Used in PAX6-Related Aniridia

Clinical Description

PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia, a congenital eye anomaly, is usually detected at birth if fully penetrant. It is often the presenting feature of WAGR; children with WAGR are at significant risk of developing Wilms tumor during early childhood.

Genotype-Phenotype Correlations

Isolated aniridia. PAX6 haploinsufficiency produces classic and severe aniridia with a high incidence of sight-reducing pathology including optic nerve malformations, glaucoma, cataract, and corneal changes [Kleinjan & van Heyningen 1998, Prosser & van Heyningen 1998, Grønskov et al 1999, Hanson et al 1999, Lauderdale et al 2000, van Heyningen & Williamson 2002, Chao et al 2003, Tzoulaki et al 2005, Dansault et al 2007, Hingorani et al 2009].

PAX6 pathogenic missense variants, particularly those that are in the paired domain and therefore likely to significantly reduce the DNA binding ability, tend to produce atypical/milder or variable-phenotype aniridia with better vision, more residual iris tissue, and a lower frequency of sight-reducing malformations and complications [Hingorani et al 2009].

C-terminal extension (CTE) pathogenic variants, which generate a longer protein product, are associated with a moderately severe aniridic phenotype with poor vision, keratopathy, and cataracts; however, individuals with CTE pathogenic variants are less likely to have glaucoma and are more likely to have preservation of iris tissue than individuals who have pathogenic null variants [Hingorani et al 2009, Aggarwal et al 2011]. For reasons that are not clear, the rare reports of significant non-foveal retinal abnormalities (exudative retinopathy, chorioretinal degeneration) are all associated with CTE pathogenic variants [Hingorani et al 2009, Aggarwal et al 2011].

Penetrance

Isolated aniridia has almost complete penetrance.

Aniridia in WAGR also has almost complete penetrance. The risk of Wilms tumor is up to 77%.

Prevalence

The prevalence of aniridia is 1:40,000 to 1:100,000. No racial or sexual differences are recognized.

The prevalence of WAGR syndrome is approximately 1:500,000.

Individuals with Aniridia and No Identifiable PAX6 Pathogenic Variant

Heterozygous pathogenic variants in the following genes are included in the differential diagnosis of PAX6-related aniridia:

• FOXC1. Phenocopies exist and include dominant alleles of FOXC1, which can cause diagnostic difficulties [Khan et al 2008, Ito et al 2009].
• PITX2. Perveen et al [2000]
• PITX3. Semina et al [1998]
• Unknown. Ansari et al [2016] could not identify the cause of aniridia in 20 individuals despite PAX6, FOXC1, and PITX2 sequence analysis, FISH, and aCGH, suggesting there may be further genetic heterogeneity with potentially new disease loci and/or novel mutational mechanisms.

Rieger anomaly, a form of anterior segment mesenchymal dysgenesis, is characterized by severe iris atrophy, corectopia (displaced pupils), iris holes, and, frequently, childhood-onset glaucoma. Rieger anomaly may be distinguished from aniridia by the presence of posterior embryotoxon (visible Schwalbe's line seen as a white line just inside the corneal limbus) with attached iris strands, relatively good visual acuity, and the absence of nystagmus or foveal abnormality.

Iris coloboma is a developmental defect resulting in a focal absence of the iris and a keyhole-shaped pupil; the rest of the iris is normal. Chorioretinal coloboma may be associated. Most iris colobomas are not associated with reduced visual acuity or nystagmus unless accompanied by a large posterior coloboma that involves the optic nerve and fovea; such large chorioretinal colobomas are apparent on fundoscopic examination.

Gillespie syndrome (OMIM 206700), characterized by partial iris hypoplasia, cerebellar ataxia, and intellectual disability, can be distinguished from aniridia by a characteristic iris configuration in Gillespie syndrome showing a scalloped pupillary edge with iris strands extending onto the anterior lens surface [Nelson et al 1997]. In five simplex cases of Gillespie syndrome (i.e., a single occurrence in a family), three were found to have biallelic ITPR1 pathogenic variants and two were found to have a de novo heterozygous ITPR1 pathogenic variant [Gerber et al 2016].

Oculocutaneous albinism (OCA) and ocular albinism typically present in early infancy with nystagmus but a structurally complete iris, typical diffuse iris transillumination (resulting from reduced pigment in the iris pigment epithelium), hypopigmented fundus, and, in the case of OCA, skin and hair hypopigmentation, which distinguish these disorders from aniridia (see Oculocutaneous Albinism Type 4 and Oculocutaneous Albinism and Ocular Albinism Overview).

The other causes of nystagmus and poor vision in infancy (e.g., retinal dysplasia, retinal dystrophy, congenital cataracts, optic nerve hypoplasia, congenital infections) lack the iris changes seen in aniridia.

Causes of partial or complete absence of iris tissue in adults include trauma, prior ocular surgery, and the iridocorneal endothelial syndromes. The age at onset, medical history, and absence of other ocular features in aniridia should prevent diagnostic confusion with aniridia.

Evaluation Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with aniridia (whether isolated or part of WAGR syndrome), the following are recommended:

• Evaluation of visual acuity (not easily performed in infants) and documentation of the degree of iris tissue deficiency, and the presence of foveal and optic nerve hypoplasia in order to predict future visual function.
• Evaluation for the degree of involvement of the cornea and lens and measurement of intraocular pressure, as they are potentially treatable causes of further visual reduction; however, treatable changes may not appear until later in life.
• Consultation with a clinical geneticist and/or genetic counselor

To establish the extent of disease and needs in an individual diagnosed with Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome, the following are recommended:

• Evaluation by a pediatrician to assess growth and feeding
• Evaluation for Wilms tumor
• Evaluation by a urologist for urogenital abnormalities
• Developmental assessment

Treatment of Manifestations

Aniridia. Simple measures are often the most important:

• Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production.
• Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted, or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film.
• Occlusion therapy in childhood for anisometropic amblyopia or strabismic amblyopia
• Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age
• Advice and help with schooling
• Social support

Note: Corrective surgery for strabismus can be undertaken to improve alignment and appearance but will not result in improved visual function.

Lens. Cataract extraction can significantly improve visual acuity in those with severe lens opacities. It should be remembered that in aniridia visual improvement after surgery is limited by foveal hypoplasia; thus, mild to moderate lens opacities may not require surgery:

• Children rarely require surgery (lensectomy).
• In adults, phacoemulsification and intraocular lens implantation can improve visual function if the cataract is severe.

Note: (1) A significant number of individuals with aniridia have poor zonular stability, which increases the risk for intraoperative complications and influences the choice of surgical technique and options for intraocular lens (IOL) implantation [Schneider et al 2003]. (2) The use of various types of black diaphragm aniridic IOLs may reduce glare or light sensitivity but are associated with a higher rate of surgical complications [Reinhard et al 2000, Menezo et al 2005, Pozdeyeva et al 2005].

Intraocular pressure

• Glaucoma is usually initially treated with topical anti-glaucoma medication.
• Surgery is reserved for eyes that do not respond to medical therapy:
  • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment.
  • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [Khaw 2002, Kirwan et al 2002, Arroyave et al 2003, Lee et al 2010].

Note: (1) Glaucoma presenting in infancy is more difficult to treat. Medical treatment is generally ineffective and surgery is required. Goniotomy and trabeculotomy have a low success rate, but trabeculectomy with or without antimetabolites is often successful [Nelson et al 1984, Okada et al 2000, Khaw 2002]. (2) While goniosurgery has been suggested as a preventive measure, glaucoma never develops in a significant proportion of those with aniridia [Swanner et al 2004].

Cornea

• Ocular surface disease can be treated medically using lubricants, mucolytics, and punctal occlusion, which may help slow the progression of sight-threatening corneal changes. Note: Drops without preservatives are often required to avoid preservative-related ocular surface toxicity.
• When corneal opacification causes significant visual reduction, penetrating keratoplasty (PK) may be considered; however, in the presence of the significant limbal stem cell deficiency observed in aniridia, PK alone has a poor prognosis [Tiller et al 2003].
• Limbal stem cell transplantation alone, preceding or concurrent with keratoplasty, may be undertaken but requires an allograft as both eyes are usually affected. This may take the form of a cultured stem cell sheet or a limbal tissue transplant [Lee et al 2008, Pauklin et al 2010]. However, this therapy is associated with a high risk of failure, and lifelong systemic immunosuppression may be required to prevent rejection. Whether the use of cultured oral mucous membrane cells may have a beneficial role is as yet uncertain.

Aniridic fibrosis syndrome. Surgical intervention is recommended at the first sign of aniridic fibrosis syndrome [Tsai et al 2005].

Wilms tumor. See Wilms Tumor Predisposition overview.

Genital abnormalities. This may need specialist care for functional and cosmetic management including endocrine therapy and surgical correction (e.g., hypospadias repair). There may be fertility issues that require support or active management.

Developmental delay / intellectual disability. There are a range of developmental, intellectual, psychiatric, and behavioral issues, as well as the challenges of visual impairment. Children may require:

• Special educational support including extra or different teaching resources and a specialized educational setting, specialist teachers of the visually impaired, educational psychologists, and formal statements of educational needs;
• Involvement of a pediatrician and sometimes a pediatric psychiatrist.

Surveillance

Agents/Circumstances to Avoid

It has been suggested that intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy [Edén et al 2010], and repeated intraocular surgery does predispose to the rare but severe aniridic fibrosis syndrome. Patients should therefore be counseled about these risks before undertaking such surgery.

Evaluation of Relatives at Risk

Early clarification of the genetic status of infants who are offspring or sibs of an individual with PAX6-related isolated aniridia (by either an eye examination or molecular genetic testing for the PAX6 variant in the family) is recommended in order to identify those who would benefit from prompt treatment and surveillance of complications of aniridia.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Ongoing research is investigating the role and success of limbal stem cell transplantation and ocular mucous membrane cell transplantation for keratopathies associated with limbal stem cell failure, including aniridia [Menzel-Severing et al 2013, Polisetti & Joyce 2013].

A Phase II randomized, double-masked, placebo-controlled study of ataluren in individuals with aniridia caused by pathogenic nonsense variants in PAX6 is under way (ClinicalTrials.gov Identifier: NCT02647359). This is based on preclinical evidence that the small-molecule drug ataluren can effectively suppress the nonsense mutation in the Pax6 mouse model, generating full-length functional protein that reversed the developmental defect following postnatal drug administration [Gregory-Evans et al 2014, Wang et al 2017].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner.

• Isolated aniridia is associated with a pathogenic variant in PAX6 or deletion of a regulatory region controlling PAX6 expression.
• WAGR syndrome is associated with contiguous-gene deletions including PAX6 and WT1.

Risk to Family Members

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the genetic alteration is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have isolated aniridia and to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Prenatal testing for a pregnancy at increased risk for PAX6-related aniridia and preimplantation genetic testing are possible if:

• A PAX6 pathogenic variant or regulatory region pathogenic variant has been identified in a proband with isolated aniridia [Churchill et al 2000];
• A deletion of PAX6 and WT1 has been identified in a proband with WAGR syndrome.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PAX6 belongs to the PAX (paired box) family of genes that code for highly conserved DNA-binding proteins believed to be important in controlling organogenesis by altering expression of other genes [van Heyningen & Williamson 2002].

Gene structure. PAX6 occupies 22 kb. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. The longest transcript encoding the longest isoform is NM_000280.4. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 470 unique PAX6 pathogenic variants have been identified, more than 90% of which are predicted to disrupt transcription or translation [Prosser & van Heyningen 1998, Tzoulaki et al 2005, Richardson et al 2016]:

• Approximately 60% are intragenic loss-of-function variants that introduce a premature termination codon and (occasionally) variants of up- or downstream regulatory sequences. This is generally associated with more severe disease including a high incidence of complications [Prosser & van Heyningen 1998, Crolla & van Heyningen 2002, Tzoulaki et al 2005, Hingorani et al 2009].
• Approximately 25% are missense variants that have been detected in less severe forms of aniridia, and that may code for nearly complete loss of protein function, or are associated with other ocular phenotypes such as isolated foveal hypoplasia [Azuma et al 1998, Vincent et al 2003, Chauhan et al 2004, Tzoulaki et al 2005, Hingorani et al 2009].
• A small percentage are C-terminal extension (CTE) variants (e.g., variants in the stop codon that extend the protein), such as c.1267dupT, which has been reported more than 20 times, are associated with more severe aniridia phenotypes, sometimes with retinal changes [Hingorani et al 2009; Richardson et al 2016].

Four CpG dinucleotides in exons 8, 9, 10, and 11 are the most common sites for pathogenic variants, accounting for 21% of all reported pathogenic variants [Tzoulaki et al 2005]. Large deletions that may involve other genes (e.g., WT1) also produce aniridia.

Many pathogenic variants have been reported in PAX6, both in aniridia and in related ocular phenotypes including Peters anomaly, foveal hypoplasia, and optic nerve anomalies:

• Of the PAX6 pathogenic variants known to cause aniridia, most lead to loss of protein function and comprise nonsense variants (39%), splice variants (13%), frameshifting deletions and insertions (25%), in-frame insertions and deletions (6%), missense variants (12%), and run-on variants (5%) [Prosser & van Heyningen 1998, Tzoulaki et al 2005].
• Of the approximately 30 known pathogenic variants for non-aniridia eye disorders, 69% are missense variants [Tzoulaki et al 2005].

Reduction of expression of alternatively spliced PAX6 protein isoforms can also cause an altered or less severe phenotype [Azuma et al 1999, Vincent et al 2003, Chauhan et al 2004].

Table 3.

PAX6 Pathogenic Variants Discussed in This GeneReview

Normal gene product. PAX6 encodes the PAX6 protein, a 422-amino-acid protein (NP_000271.1) that acts as a transcription factor. PAX6 contains a paired domain and a paired-type homeodomain, both with DNA-binding capability, separated by a lysine-rich linker region. A C-terminal proline, serine, and threonine-rich (PST) domain acts as a transcriptional activator.

PAX6 protein is thought to act as the major controller of ocular development during embryogenesis by effects on cellular proliferation, differentiation, migration, and adhesion; several target genes have been identified [van Heyningen & Williamson 2002]. PAX6 protein expression continues in the adult retina, lens, and cornea and may help maintain good ocular health [Koroma et al 1997, van Heyningen & Williamson 2002].

Various isoforms of PAX6 protein are derived through alternative splicing (PAX6-ex12, PAX6-5a,6', PAX6-5a). The ratios of these isoforms may be critical to normal ocular development [Singh et al 2002].

Abnormal gene product. Heterozygous pathogenic variants of PAX6 appear to disturb ocular morphogenesis, resulting in aniridia and related ocular phenotypes, and also may produce mild central nervous system defects [Sisodiya et al 2001, Free et al 2003, Ellison-Wright et al 2004, Valenzuela & Cline 2004]. Homozygous or compound heterozygous loss of PAX6 function leads to anophthalmia and central nervous system defects, which are often fatal [Hodgson & Saunders 1980, Glaser et al 1994, Schmidt-Sidor et al 2009].

WAGR syndrome is caused by either cryptic or cytogenetically visible deletions involving varying amounts of 11p that include band 11p13 with PAX6 and neighboring genes. The loss of WT1 produces genitourinary and renal abnormalities and predisposes to Wilms tumor, which results from loss of heterozygosity. Deletion of one copy of PAX6 causes aniridia.

Yamamoto et al [2014] describe an individual with an unusual deletion split into two regions on chr11p13 – a 2.2-Mb and a 10.5-Mb deletion with PAX6 and PRRG4 preserved at normal copy number between them – who did not have WAGR or autistic behavior. They suggest that haploinsufficiency of PAX6 or PRRG4 is responsible for intellectual disability and autistic features associated with WAGR.

Revision History

• 18 October 2018 (bp) Comprehensive update posted live
• 14 November 2013 (me) Comprehensive update posted live
• 12 July 2008 (me) Comprehensive update posted live
• 15 July 2005 (me) Comprehensive update posted live
• 20 May 2003 (me) Review posted live
• 2 September 2002 (am) Original submission

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