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

3006247

Angelman Syndrome and Prader-Willi Syndrome by Methylation-Specific MLPA 3006247

Method

Qualitative /Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA)

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
Finding	Interpretation
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 karyotyping^a
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 rearrangement^a
Paternally and maternally contributed AS/PWS critical regions detected, with abnormal copy number consistent with duplication	This 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
Finding	Interpretation
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

GeneReviews - Angelman Syndrome

Dagli AI, Matthews J, Williams CA. Angelman syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Updated Apr 2021; accessed Jul 2024.

GeneReviews Prader-Willi Syndrome - PWS

Driscoll DJ, Miller JL, Cassidy SB, et al. Prader-Willi syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Updated Mar 2023; accessed Jul 2024.

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