Angelman Syndrome and Prader-Willi Syndrome Testing

  • Preferred initial diagnostic test for AS or PWS
  • Establish diagnosis in individuals with clinical symptoms
  • Second-tier test for the diagnosis of AS
  • Order if suspicion for AS remains after normal methylation analysis
  • Establish diagnosis in individuals with clinical symptoms of AS and normal DNA methylation
  • Prenatal testing for AS or PWS
  • Identifies cases resulting from molecular mechanisms that produce abnormal methylation patterns

Follow-up for abnormal methylation test for AS

Follow-up for abnormal methylation test for AS

Rule out an MECP2 gene mutation in individuals with clinical features of AS who lack a molecular abnormality involving 15q11.2-q13

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: one in 12,000-24,000
  • PWS: one 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

  DNA Methylation UBE3A Gene Sequencing
Clinical sensitivity

AS: ~80%

PWS: >99%

AS: 11%

PWS: n/a

Analytical sensitivity

99%

99%

Positive result

Absence of appropriate methylated parental allele confirms diagnosis

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
  • 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

Confirms diagnosis of AS in symptomatic individual

Inconclusive result

n/a

Gene variant detected, but whether the variant is benign or pathogenic is unclear

Limitations

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

Diagnostic errors can occur due to rare sequence variations

Regulatory mutations, deep intronic mutations, and large deletions/duplications will not be detected

Diagnostic errors may occur due to rare sequence variations

n/a, not applicable

    References