SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
print        

Angelman Syndrome (AS)

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

Background

Angelman syndrome (AS) is characterized by severe developmental delay or mental retardation, severe speech impairment, gait ataxia and/or tremors in the limbs. Microcephaly and seizures are common. Affected individuals also display characteristic demeanor that includes inappropriate laughing, smiling, and excitability.

There are a number of genetic changes that cause AS, although each produces a similar clinical phenotype. Approximately 70% of cases are the result of a deletion in the maternally contributed chromosome 15q11-q13 region. Approximately 5% of cases have received two copies of chromosome 15 from their father and none from their mother: paternal uniparental disomy (patUPD). Like the deletion patients, paternal UPD patients are deficient for maternally derived genes in the AS critical region. Approximately 5% of patients have an 'imprinting mutation' which alters the normal expression of maternal genes in the AS critical region. Approximately 20% of clinically diagnosed AS patients have genetic alterations other than deletion, UPD or imprinting mutations. These mutations are not detected by methodology currently in place in the Molecular Genetics Laboratory, and samples may be referred to a research lab for further investigation.

DNA in the AS 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. Testing the methylation status of genes within the critical region therefore allows these genetic alterations to be detected. For molecular analysis, the methylation status of the gene SNRPN within the AS critical region is measured. Abnormal methylation of the maternally derived gene is diagnostic of Angelman syndrome.

Who should be tested?

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

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 maternal allele expression is due to paternal UPD or imprinting mutations. Highly polymorphic DNA marker alleles associated with the AS 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 maternal alleles is due to deletion, paternal UPD, or imprinting mutations in approximately 80% of individuals affected with AS. These cases will be detected by current testing procedures in place in the Molecular Genetics Laboratory.

  • Approximately 20% of AS patients have genetic alterations other than deletion, UPD or imprinting mutations. These individuals will not be diagnosed by this analysis.For
    •  example, of 10 people with Angelman syndrome, direct methylation analysis will confirm the diagnosis in approximately 8 people, but will not confirm the diagnosis in 2 people.
AS_MS-MLPA image

 

Potential Outcomes & Interpretation of Test Results

SNRPN Methylation Status

Interpretation

normal methylation

  • This result does not support a diagnosis of Angelman syndrome.

abnormal methylation

  • This result confirms a diagnosis of Angelman syndrome.

Deletion detected

  • This result confirms a diagnosis of Angelman syndrome.

Cautions

  1. Rare cases of AS result from a subtle balanced translocation involving one of the parents. These will not be detected by the diagnostic procedures used in the Molecular Genetics Laboratory. Identification of these cases is important for assessment of recurrence risk.
  2. AS may be caused by point mutations or small deletions in the AS critical region of chromosome 15. 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 AS.
  3. 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