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Beckwith - Wiedemann Syndrome

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

Beckwith-Wiedemann syndrome (BWS) is a growth disorder characterized by a number of features, including large body size, defects in the closure of the abdominal wall during development, and an enlarged tongue. A variety of other features may also present. Patients with BWS also show a significantly increased incidence of childhood tumours, especially Wilms’ tumor.

In 85 per cent of cases, there is no family history of BWS. However, in approximately 15 per cent of cases, BWS is transmitted from one generation to the next. In these families, BWS is inherited in an autosomal dominant fashion, usually through the mother. There is no way to predict which or how many of the features characteristic of BWS will be present in an individual with the mutation.

There are a number of genetic changes that cause BWS. To date, all of these occur on chromosome 11 at 11p15.

Methylation at KvDMR and H19
Methylation abnormalities at differentially methylated regions (DMR) in the 11p15 region have been shown to cause BWS. KCNQ1OT1 is a maternally imprinted non-coding antisense transcript. The 5’ region of KCNQ1OT1 (KvDMR) is differentially methylated. Normally, the maternally derived chromosome is methylated, whereas the paternally derived chromosome is unmethylated. Loss of maternal methylation at KvDMR is observed in 50- 60 per cent of individuals with BWS. H19 is a paternally imprinted gene encoding a biologically active non-coding transcript that may function as a tumour suppressor. Normally, the paternally derived chromosome is methylated and the maternally derived chromosome is unmethylated. Gain of maternal methylation at H19 is observed in ~5 per cent of BWS cases. For molecular analysis, the methylation status at KvDMR and H19 is measured. Individuals with UPD can be distinguished from individuals with abnormal methylation of either KvDMR or H19 since those with UPD have methylation abnormalities at both KvDMR and H19. If the methylation results are normal at both KvDMR and H19, this result indicates normal biparental contributions in the tissue sample tested (N.B. see Sensitivity of the Test below).

UPD 11
Approximately 10-20 per cent of BWS cases have received two copies of the 11p15 region from their father and none from their mother, which is called paternal uniparental disomy (patUPD). Paternal UPD patients have an imbalance of gene expression in the BWS critical region. Dosage analysis of paternal and maternal genes in the BWS critical region can be used to detect UPD.

CDKN1C
Patients with BWS may also have mutations in the CDKN1C (p57) gene. The CDKN1C gene is a member of the cyclin-dependent kinase inhibitor family, which acts to negatively regulate cell proliferation. Mutations in the CDKN1C gene have been reported in approximately 5-10 per cent of BWS cases with no known family history and in approximately 40 per cent of cases in inherited autosomal dominant families.

Who should be tested?

• Individuals/pregnancies clinically suspected of being affected with BWS

Testing Methodology

Methylation Status Analysis: Southern blot analysis is used to determine the methylation status at KvDMR and H19.

Sensitivity of the Test: There is an abnormal methylation expression at KvDMR in 50-60 per cent of BWS cases, an abnormal methylation at H19 in ~5 per cent of the cases and paternal UPD in 10-20 per cent of patients. These cases will be detected by current testing procedures in place in the Molecular Genetics Laboratory.

Dosage Analysis: A PCR-based dosage assay is used to confirm paternal UPD in any individual who has methylation abnormalities at both KvDMR and H19. Dosage analysis compares the quantity of genetic material from each parent in the BWS critical region to determine if the amount of genetic material from the mother equals the amount from the father. If the amount from the father is greater than from the mother, BWS due to UPD is a possibility.

Sensitivity of the Test: Approximately 10-20 per cent of patients with BWS show paternal UPD of region 11p15 on chromosome 11. Most of these cases will be detected by current testing procedures in place in the Molecular Genetics Laboratory.

• • Of the patients with BWS who have UPD as the underlying cause, a small proportion may yield a negative result due to low-level mosaicism.

Direct Mutation Analysis: Patient samples are analyzed by direct sequencing to detect mutations in the coding region (exon 1 & 2) of the CDKN1C (p57) gene. 

• • A mutation will be detected in 5-10 per cent of patients with no family history of BWS. 
  • A mutation will be detected in approximately 40 per cent of patients with a family history of BWS.

Note: Approximately 15 per cent of BWS patients may have other genetic alterations than above mentioned mutations that are not detected by the testing currently available. These genetic alterations are not currently assessed in the Molecular Genetics Laborator

Potential Outcomes & Interpretation of Test Results

Note: Individuals with UPD can be distinguished from individuals with abnormal methylation of either KvDMR or H19 because those with UPD have methylation abnormalities at both KvDMR and H19.

Cautions

• All cases of BWS warrant a cytogenetic analysis to rule out chromosome translocations and duplications.
• Parental samples are required to confirm paternal UPD in cases where a dosage discrepancy is detected in the patient.
• For CDKN1C mutation analysis it is helpful to first identify the mutation in an affected family member or in the parent of the affected family member. If the familial mutation can be identified in this way, the molecular test is conducted only for the familial mutation.
• A negative molecular test result does not rule out the diagnosis of BWS. BWS patients may have genetic alterations other than KvDMR, H19, UPD and CDKN1C mutations.
• These molecular alterations are not currently assessed in the Molecular Genetics Laboratory, and may be referred to a research lab for further investigation.
• To date, most patients with BWS and UPD for 11p15 have shown somatic mosaicism, where some cells have UPD while others do not. Levels of mosaicism less than 20 per cent will not be detected by the methodologies in place in the Molecular Genetics Laboratory. If a diagnosis of BWS is still highly suspected, samples of other tissues (e.g. skin fibroblasts) should be submitted for analysis.
• As BWS patients may have tissue specific alterations, the test results are specific for the sample/tissue type tested. If a diagnosis of BWS is still highly suspected after a normal result, analysis of samples from other tissues (e.g. skin fibroblasts) may be warranted.
• This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

For More Information:

• Online Mendelian Inheritance in Man
  • Item #130650
• GeneReviews online clinical information resource
  • Funded by the U.S.National Institutes of Health, Developed at the University of Washington, Seattle
• Cancernet
• To locate a genetics center near you, please visit Canadian Association of Genetic Counsellors Website.