Angelman Syndrome and Prader-Willi Syndrome by Methylation-Specific MLPA

Last Literature Review: April 2023 Last Update:
  • Preferred initial diagnostic test for AS or PWS
  • Use to establish a diagnosis in individuals with clinical symptoms
  • Prenatal testing for AS or PWS to identify cases resulting from molecular mechanisms that produce abnormal methylation patterns

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are complex neurodevelopmental disorders characterized by developmental delay, as well as symptoms unique to each disorder (eg, distinctive happy demeanor in AS, hyperphagia 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 of age , 
  • PWS: Neonatal , 

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)
  • Imprinting center defect
  • Unbalanced chromosome translocation
  • UBE3A gene mutation (AS only)
  • Unidentified (AS only)

For more information about the underlying mechanisms of AS and PWS, refer to the ARUP Consult Angelman Syndrome and Prader-Willi Syndrome 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.
  • Testing of chorionic villus samples is not recommended as methylation may be incomplete in early embryonic development.

Test Interpretation

Clinical Sensitivity

  • >99% for PWS 
  • 80% for AS 

Analytic Sensitivity

99% for PWS and AS

Results

Positive Result
FindingInterpretation
Maternally contributed AS/PWS critical region only, with normal copy number
  • Confirms a diagnosis of PWS
  • Order DNA polymorphism analysis to distinguish between UPD and imprinting defect
Maternally contributed AS/PWS critical region only, with abnormal copy number consistent with deletion
  • Confirms a diagnosis of PWS
  • Consider chromosome analysis for proband to exclude rare rearrangement and to determine the need for paternal/maternal karyotypinga
Paternally contributed AS/PWS critical region only, with normal copy number
  • Confirms a diagnosis of AS
  • Order DNA polymorphism analysis to distinguish between UPD and imprinting defect
Paternally contributed AS/PWS critical region only, with abnormal copy number consistent with deletion
  • Confirms a diagnosis of AS
  • Consider both chromosome analysis and fluorescence in situ hybridization (FISH) in mother to exclude rare rearrangementa
Paternally and maternally contributed AS/PWS critical regions detected, with abnormal copy number consistent with duplicationThis assay is not validated to detect increased copy number of 15q11.2-q13 or determine parent of origin for duplications
aAlters recurrence risk. Refer to the ARUP Consult Angelman Syndrome and Prader-Willi Syndrome topic for more information.
Negative Result
FindingInterpretation
Normal methylation pattern of both maternally and paternally contributed AS/PWS critical regions with normal copy number
  • Greatly reduces the probability of a PWS diagnosis; <1% of individuals with PWS have normal methylation patterns
  • Reduces, but does not exclude, the probability of an AS diagnosis; approximately 20% of individuals with AS have normal methylation patterns

Limitations

  • Disease mechanisms causing AS that do not alter methylation patterns will not be detected.
  • Diagnostic errors can occur due to rare sequence variations.
  • This assay is not validated to detect increased copy number of 15q11.2-q13 or determine parent of origin for duplications.
  • This assay cannot distinguish between UPD and imprinting defects causative of PWS and AS.
  • AS and PWS mosaicism will not be assessed by this assay.
  • Interpretation of this test result may be impacted if the proband has had an allogeneic stem cell transplantation.
  • Methylation patterns may not be fully established in early gestation; thus, diagnostic testing on chorionic villus samples is not recommended.

References