Angelman Syndrome and Prader-Willi Syndrome Testing

  • Preferred initial diagnostic test for AS or PWS
  • Use to establish a diagnosis in individuals with clinical symptoms
  • Prenatal testing for AS or PWS
  • Use to identify cases resulting from molecular mechanisms that produce abnormal methylation patterns
Related Tests

Follow-up for abnormal methylation test for AS

Follow-up for abnormal methylation test for AS

Useful when a pathogenic familial variant identifiable by sequencing is known.

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are complex neurodevelopmental disorders characterized by developmental delay and intellectual disability, as well as symptoms unique to each disorder (eg, unique happy demeanor in AS, excessive eating in PWS). Both conditions are linked to loss of function of genes in the 15q11.2-q13 region.

Disease Overview

Prevalence

  • AS: 1 in 12,000-24,000
  • PWS: 1 in 10,000-30,000

Age of Onset

  • AS: 6-12 months
  • PWS: Neonatal

For more information about the clinical characteristics of AS and PWS, see the Angelman Syndrome and Prader-Willi Syndrome Consult topic.

Genetics

Genes

15q11.2-q13 region

Etiologies

  • Deletion of 15q11.2-q13 (AS: maternal; PWS: paternal)
  • Uniparental disomy (UPD) for chromosome 15 (AS: paternal; PWS: maternal)
  • UBE3A gene mutation (AS only)
  • Imprinting center defect
  • Unbalanced chromosome translocation
  • Unidentified (AS only)

For more information about the underlying mechanisms of AS and PWS, see the Angelman Syndrome and Prader-Willi Syndrome Consult topic.

Prenatal Screening

  • Prenatal testing is recommended for subsequent pregnancies of couples who have a previous child with AS or PWS.
  • Parental testing does not exclude somatic and/or germline mosaicism.
  • Methylation testing is not offered on chorionic villus samples.
  • Incomplete methylation in early embryonic development may cause false-positive results.

Test Interpretation

Sensitivity

  DNA Methylation UBE3A Gene Sequencinga

Clinical sensitivity

AS: ~80%

PWS: >99%

AS: 11%

PWS: n/a

Analytical sensitivity

99%

99%

aTest is not performed at ARUP Laboratories.

Results 

  DNA Methylation

Positive result

Abnormal methylation pattern of maternally (PWS) or paternally (AS) contributed AS/PWS critical region is present

Confirms diagnosis of AS or PWS

Follow up with fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (CGH) to determine whether deletion is present

  • If large deletion is present
    • Order chromosome analysis in parent to exclude rearrangement (alters recurrence risk; see AS and PWS Consult topic)
  • If FISH is normal
    • Order DNA polymorphism analysis to distinguish between UPD and imprinting defect
  • If no UPD
    • Order further DNA studies to detect imprinting defect

Testing of both parents may be necessary

Inconclusive result

n/a

Negative result

Normal methylation pattern of both maternally and paternally contributed AS/PWS critical regions

Reduces, but does not exclude, the probability of an AS diagnosis (~20% of individuals with AS have normal methylation patterns)

Greatly reduces the probability of a PWS diagnosis (99% of individuals with PWS have abnormal methylation patterns)

n/a, not applicable

Limitations

DNA Methylation

  • Specific molecular mechanism responsible for abnormal methylation results cannot be determined via this test alone.
  • AS or PWS resulting from molecular mechanisms that do not affect methylation patterns will not be identified.
Additional Resources