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Prader-Willi Syndrome (PWS)

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

Background

Prader-Willi syndrome (PWS) is characterized by severe muscle weakness, feeding difficulties and failure to thrive in early infancy, followed in later infancy by uncontrolled appetite and severe obesity. All patients have some degree of mental retardation and behavior problems are common. In addition, PWS patients show short stature, small hands and feet and undescended testes in males.

There are a number of genetic changes that cause PWS, although each produces a similar clinical phenotype. Approximately 70-75 per cent of PWS cases are the result of a deletion of the paternal copy of the PWS critical region on chromosome 15. Approximately 25 per cent of cases have received two copies of chromosome 15 from their mother and none from their father, maternal uniparental disomy (matUPD). Like the deletion patients, the UPD patients are deficient for paternally derived genes in the PWS critical region. Approximately five per cent of patients have an ‘imprinting mutation’ which alters the normal expression of paternal genes in the PWS critical region.

DNA in the PWS critical region is methylated. If the normal expression of genes in the critical region is altered due to deletion, UPD or imprinting mutations, the methylation pattern is also changed. Therefore, testing the methylation status of genes within the critical region allows these genetic alterations to be detected. For molecular analysis, the methylation status of the gene SNRPN within the PWS critical region is measured. Abnormal methylation of the paternally derived genes is diagnostic of Prader-Willi syndrome. Point mutations or genetic rearrangement in the critical region, although very rare, may also result in PWS despite normally methylated paternal and maternal genetic contributions. These mutations are not detected by methodology currently in place in the Molecular Genetics Laboratory.

Who should be tested

• individuals clinically suspected of being affected with PWS
• pregnancies at risk due to a family history of PWS

Testing Methodology

Gene Dosage Analysis: Multiplex Ligation-dependent Probe Amplification (MLPA) analysis is used to determine the methylation status of SNRPN.

STR Analysis: STR analysis can be used to determine if the lack of paternal allele expression is due to maternal UPD or imprinting mutations. Highly polymorphic DNA marker alleles associated with the PWS critical region in the affected individual are compared to the pattern of markers in the parents to determine the parental origin and genetic nature of the disorder.

Test Sensitivity: Abnormal expression of paternal alleles is due to deletion, maternal UPD, or imprinting mutations in approximately 99 per cent of individuals affected with PWS. These cases will be detected by current testing procedures in place in the Molecular Genetics Laboratory.

• A very small number of PWS patients have genetic alterations other than deletion, UPD or imprinting mutations. These individuals will not be diagnosed by this analysis.
• For example, of 100 people with Prader-Willi Syndrome, 99 will be detected by this test; 1 will not be detected.

Potential Outcomes & Interpretation of Test Results

Cautions:

• Rare cases of PWS result from a subtle genetic rearrangement involving one of the parents. These will not be detected by the diagnostic procedures used in the Molecular Genetics Laboratory. Identification of these cases can be done by cytogenetic analysis.
• PWS may be caused by point mutations or small deletions in the PWS critical region of chromosome 15 (15q11-q13). These changes will not be detected by the diagnostic procedures used in the Molecular Genetics Laboratory. A negative molecular test result does not rule out a clinical diagnosis of PWS.
• 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 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:

• Prader Willi Research Canada
• To locate a genetics center near you, please visit Canadian Association of Genetic Counsellors website.