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WAGR syndrome; Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome; chromosome 11p13 deletion syndrome.
607102 (WT1), 607108 (PAX6).
Breakpoints differ in individual cases, but the minimum deletion involves both PAX6 and WT1, which are ~700kb apart in the distal half of band 11p13.
Analyze known non-deleted and deleted cases in parallel as controls to show that reagents used for FISH, array CGH and MLPA are working well.
(Incidence at birth (‘birth prevalence') or population prevalence):
Rare, with only a few hundred cases reported.
(proportion of positive tests if the genotype is present)
Essentially 100% with appropriate FISH probes, MLPA or array CGH. Cytogenetic analysis is less sensitive and, if normal, one of the above methods must be used. Very rarely mosaic sub-microscopic deletions will reduce the analytical sensitivity of MLPA and array CGH but not the use of appropriate FISH probes.
(proportion of negative tests if the genotype is not present)
Essentially 100% with appropriate FISH probes, MLPA or array CGH.
(proportion of positive tests if the disease is present)
The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.
Nearly 100% if sporadic aniridia and Wilms tumor, male genitourinary abnormalities or significant nephropathy is present. If sporadic aniridia alone is present (eg, a newborn female), then 10–30% have WAGR syndrome (data limited by small numbers).3
(proportion of negative tests if the disease is not present)
The clinical specificity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case. It is worthwhile pointing out that other 11p13 deletions that include WT1 but do not involve PAX6 can occur. Therefore, for patients without aniridia but for whom WT1 deletion is suspected (eg, a patient with Wilms tumor, genitourinary abnormalities and cognitive impairment), genetic testing for 11p13 deletion is recommended.
Essentially 100% if aniridia is not present.
(lifetime risk to develop the disease if the test is positive)
Essentially 100% for aniridia (which is congenital), other features due to WT1 gene deletion are variable. In all, 42.5–77% have been shown to develop Wilms tumor depending on the deletion size. End-stage renal disease develops in 47% of WAGR patients with Wilms tumor by 20 years after diagnosis and also occurs in those without WT. Individuals with XY genotype and intra-abdominal gonads have a high risk of gonadoblastoma and should undergo gonadectomy. XY individuals with descended testes must undergo regular examination for testicular tumors. Individuals with XX genotype have also developed gonadoblastoma and should be screened by imaging.4, 5
(probability not to develop the disease if the test is negative).
Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.
Index case in that family had been tested:
Essentially 100% if no aniridia.
Index case in that family had not been tested:
Essentially 100% if no aniridia.
(To be answered if in 1.10 ‘A' was marked)
(To be answered if in 1.10 ‘B' was marked)
If the test result is positive (please describe)
See 3.1.4 for management if test result is positive.
If the test result is negative (please describe)
If test result is negative, eg, a sporadic aniridia patient does not have a WT1 deletion, then monitoring for genitourinary complications, including Wilms tumor, is not warranted.
An individual with sporadic aniridia should undergo screening for Wilms tumor by renal ultrasound and urinalysis every 3 months until 6 years and daily caretaker abdominal examination. Renal disease should be screened for by annual blood pressure and urinalysis for proteinuria beginning in early adolescence and through adulthood. There is also risk for gonadoblastoma (see 2.5 above).8
(To be answered if in 1.10 ‘C' was marked)
There are rare instances of familial recurrence of WAGR syndrome due to inherited chromosomal rearrangements or submicroscopic WAGR deletions. Parents and all at-risk relatives (determined by pedigree analysis) should be evaluated for a WAGR-associated chromosomal rearrangement or sub-microscopic deletion.9, 10
Yes, for prenatal diagnosis in the event of a familial chromosomal rearrangement or inherited sub-microscopic deletion.
(To be answered if in 1.10 ‘D' was marked)
An individual with WAGR syndrome has ~50% chance of passing on the deleted chromosome to the offspring. Prenatal testing for the parental deletion or chromosome rearrangement should be offered.
Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe).
Yes. In addition to the value of understanding the cause and recurrence risk of the disorder, many families have benefited greatly from joining the International WAGR Syndrome Association support group (http://www.wagr.org) and meeting other families. This support group has been instrumental in gathering data about the natural history of WAGR syndrome and stimulating research.
This work was supported by EuroGentest, an EU-FP6-supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical genetics, community genetics and public health', Workpackage 3.2).
The authors declare no conflict of interest.