FeedbackMethylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring
- Preferred initial diagnostic test for AS or PWS
- Use to establish a diagnosis in individuals with clinical symptoms
Polymerase Chain Reaction/Sequencing
- Second-tier test for the diagnosis of AS
- Order if suspicion for AS remains after normal methylation analysis
- Use to establish a diagnosis in individuals with clinical symptoms of AS and normal DNA methylation
Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring
- Prenatal testing for AS or PWS
- Use to identify cases resulting from molecular mechanisms that produce abnormal methylation patterns
Fluorescence in situ Hybridization (FISH)
Follow-up for abnormal methylation test for AS
Genomic Microarray (Oligo-SNP Array)
Follow-up for abnormal methylation test for AS
Sequencing/Multiplex Ligation-dependent Probe Amplification
Rule out an MECP2 gene mutation in individuals with clinical features of AS who lack a molecular abnormality involving 15q11.2-q13
Polymerase Chain Reaction/Sequencing
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
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 |
||
GeneReviews - Angelman Syndrome
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GeneReviews Prader-Willi Syndrome - PWS
Driscoll DJ, Miller JL, Schwartz S, et al. Prader-Willi syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Dec 2017; Accessed: Sep 2020]
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Goldstone AP, Holland AJ, Hauffa BP, et al. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93(11):4183-4197.
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Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2019;27(9):1326-1340.
