The Genetics of Aniridia


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The Genetics of Aniridia

  1. 1. The Genetics of Aniridia Kelly Trout, RN, BSN International WAGR Syndrome Association In terms of inheritance, there are four basic "types" of aniridia. These are: 1) Familial aniridia This is the most common form of aniridia. It is inherited directly from a parent who has aniridia. It is the result of a mutation in a gene called the “PAX6” gene. In the past, genetic testing was thought to be unnecessary for those with familial aniridia. Newer research has demonstrated that in some cases, familial aniridia may be inherited through complex genetic abnormalities (such as translocations or deletions) and that these abnormalities may result in serious conditions in the offspring. For this reason, genetic analysis and counseling should be offered to all individuals with aniridia. Each child of a person with familial aniridia will have an approximate 50% chance of inheriting the gene mutation. 2) Sporadic aniridia This type of aniridia is the second most common form. Both parents have normal chromosomes. The affected person has a “new” mutation of the PAX6 gene (a mutation which occurred before or very soon after conception). The cause of this mutation is not known.
  2. 2. Children born with sporadic aniridia should be referred for genetic testing. This testing should include high level studies (lymphocyte high resolution chromosome study of at least 550 bands, and “FISH” studies) to determine whether WAGR syndrome (see below) or other risk for Wilms tumor is present. Children with sporadic aniridia should also be followed for the development of Wilms tumor (a type of cancer of the kidney), regardless of the results of genetic testing. People with sporadic aniridia have an approximate 50% chance of passing on this condition to their children. 3) WAGR Syndrome This type of Aniridia is rare. Both parents have normal chromosomes. The affected person has a “new” mutation (as in sporadic aniridia, above). Unlike sporadic aniridia, this new mutation involves not only the PAX6 gene, but a large number of neighboring genes as well. This genetic abnormality is called a “deletion,” or set of missing genes, which are located on the short arm of chromosome number 11. High level genetic testing (lymphocyte high resolution chromosome study of at least 550 bands, along with “FISH” studies) will reveal the WAGR deletion if it is present. In addition to aniridia, children with WAGR syndrome have a high risk for Wilms tumor (a type of cancer of the kidney) and other conditions, such as genital abnormalities, cognitive impairment, and learning and behavior difficulties. There has been a single report of two cases of WAGR syndrome occurring within a family. Genetic testing will help parents determine their own risk for having another child with WAGR syndrome. To date, there have been no reports of people with WAGR syndrome having children of their own. 4) Gillespie Syndrome This type of aniridia is extremely rare. It is thought that Gillespie syndrome may be inherited through parents who do not have aniridia themselves, but who both have one normal copy of the PAX6 gene, and one mutated copy. This mode of inheritance has not been confirmed. Gillespie syndrome is associated with a “scalloped border” appearance of the iris. Learning difficulties, cognitive impairment, and cerebellar ataxia, (muscle incoordination) are also associated with Gillespie syndrome. There are reports of more than one case of Gillespie syndrome in a family. There have also been reports of people with Gillespie syndrome whose children also have the disorder. References Clericuzio C, D'Angio GL, Duncan M, Green DM, Knudson AG, Jr. 1993. Summary and Recommendations: First International Conference on
  3. 3. Clinical and Molecular Genetics of Childhood Renal Tumors. Med Pediatr Oncol 21:233-236. Crolla JA, van Heynigen V. 2002. Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. Am J Hum Genet 71:1138-1149. Fantes JA, Bickmore WA, Fletcher JM, Ballesta F, Hanson IM, van Heynigen V. 1992. Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization. Am J Hum Genet 51:1286-1294. Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M. 2005. WAGR syndrome: a clinical review of 54 cases. Pediatrics 116(4):984-8. Gillespie F. 1965. Aniridia, cerebellar ataxia and oligophrenia in siblings. Arch Ophthalmol 73:338-341. Glaser T, Ton CC, Mueller RF, Petzl-Erler ML, Oliver C, Nevin NC, Housman DE, Maas RL. 1994. Absence of PAX6 gene mutations in Gillespie syndrome (partial aniridia, cerebellar ataxia and mental retardation). Genomics 19:145-148. Miller RW, Fraumeni JFJ, Manning MD. 1964. Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital anomalies. N Engl J Med 270:922-7. Muto R, Yamamori S, Ohashi H, Osawa M. 2002. Prediction by FISH analysis of the occurrence of Wims tumor in aniridia patients. Am J Med Genet 108:285-289. Robinson DO, Howarth RJ, Williamson KA, van Heyningen V, Beal SJ, Crolla JA. 2008. Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia. Am J Med Genet A 146(5):558-69. Schinzel A. 2001. Catalogue of Unbalanced Chromosome Aberrations in Man. New York: Walter de Gruyter. Traboulsi EI, Zhu D, Maumenee IH. 1998. Aniridia. Genetic Diseases of the Eye. New York: Oxford University Press. p 99-114. Turleau C, de Grouchy J, Tournade MF, Gagdanoux MF, Junien C. 1984. Del 11p/aniridia complex. Report of three patients and review of 37 observations from the literature. Clin Genet 26:356-362. van Heyningen V, Hoovers JM, de Kraker J, Crolla JA. 2007. Raised risk of Wilms tumour in patients with aniridia and submicroscopic WT1 deletion. J Med Genet 44(12):787-90. Last reviewed: March, 2009