Angelman Syndrome and Prader-Willi Syndrome

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are complex neurodevelopmental genetic disorders characterized by developmental delay and intellectual disability. AS is caused by the loss of function of maternally inherited genes within 15q11.2-q13 due to deletion, paternal uniparental disomy, ubiquitin-protein ligase E3A (UBE3A) gene mutations, imprinting defects, translocation defects, or unknown causes. PWS is caused by loss of function of paternally expressed genes in the same region (15q11.2-q13) due to deletions, maternal uniparental disomy, chromosome translocation, or imprinting defects. Laboratory testing can be used to make a definitive diagnosis of PWS or AS, which is crucial for early intervention. Laboratory testing is also used to identify the disease mechanism, which is important for determining recurrence risk.

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Clinical Overview

Quick Answers

What are the symptoms of Angelman syndrome and Prader-Willi syndrome?

Both Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are associated with developmental delay and intellectual disability. AS is characterized by features such as ataxia, lack of speech, and a “happy” demeanor marked by frequent laughter, smiling, and excitability. Patients with AS frequently have microcephaly and seizures. PWS is associated with severe hypotonia and feeding difficulties in infancy, with gradual development of hyperphagia and morbid obesity in early childhood, as well as short stature, hypogonadism, maladaptive and compulsive behaviors, and other symptoms.

What are the genetic mechanisms that lead to Angelman syndrome or Prader-Willi syndrome, and why are they important to identify?

Most cases of Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are not inherited; rather, they are due to loss of function of genes in the 15q11.2-q13 region caused by a spontaneous deletion or uniparental disomy. In addition to spontaneous deletion and paternal uniparental disomy, 11% of AS cases are linked to pathogenic variants in the UBE3A gene, which may be heritable; rare cases are linked to chromosomal translocations/rearrangements, uniparental disomy with a parental translocation, or imprinting defects with deletions in the imprinting center, all of which may be heritable. Approximately 10% of AS cases arise from currently unknown mechanisms. As with AS, rare cases of PWS may result from potentially heritable chromosomal translocations/rearrangements, uniparental disomy with a parental translocation, and imprinting defects with deletions in the imprinting center. However, PWS is not associated with variants in UBE3A or any unknown mechanisms. Although identification of the mechanism of AS or PWS does not affect treatment, it can help determine risk of recurrence in future offspring; therefore, it is important for genetic counseling purposes.

When is prenatal testing for Angelman syndrome or Prader-Willi syndrome appropriate?

Although the risk of recurrence is very low in the case of a spontaneous 15q11.2-q13 deletion or most cases of uniparental disomy, prenatal testing may be offered following confirmed diagnosis in a family member for reassurance, especially since a negative maternal test does not exclude the small possibility of somatic and/or germline mosaicism. It is recommended that prenatal testing be offered if a heritable mechanism for Angelman syndrome (AS) and Prader-Willi syndrome (PWS) has been identified because of the high risk of recurrence. Methylation analysis, fluorescence in situ hybridization (FISH), and other techniques can be used, preferably on amniotic cells. Methylation testing is not recommended on chorionic villus samples due to incomplete methylation in early embryonic development, which may cause false-positive results; however, other molecular mechanisms responsible for AS or PWS, such as sequence variants, deletions, or chromosomal translocations, may be reliably detected in a chorionic villus sample by targeted Sanger sequencing, cytogenetic single nucleotide polymorphism microarray (CMA-SNP), or karyotyping, respectively.

Will laboratory testing diagnose all cases of Angelman syndrome?

DNA methylation testing has a clinical sensitivity of ~78%, and UBE3A gene sequencing has a sensitivity of 11% for Angelman syndrome (AS). Laboratory testing will not always confirm a clinical diagnosis of AS because some cases are caused by a currently unknown mechanism. For more information on the clinical and analytical sensitivity of AS testing, see the Angelman Syndrome and Prader-Willi Syndrome Test Fact Sheet.

Testing for Genetic Syndromes Related to Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Indications for Testing

Laboratory testing for AS and PWS can be used to:

Diagnose AS or PWS in infants or children with symptoms
Determine the risk of recurrence in future offspring of parents of a child diagnosed with AS or PWS
Monitor comorbidities and the effects of treatment in PWS

Laboratory Testing

Diagnosis and Determination of Recurrence Risk

Diagnosis of AS or PWS is based on clinical criteria. Laboratory testing confirms a diagnosis of PWS in >99% of cases, whereas the diagnosis of AS can be supported by laboratory testing in ~90% of cases. The same methods used for diagnosis can be used to identify the disease mechanism, which facilitates determination of recurrence risk.

Summary of Recommended Laboratory Testing Strategy in AS/PWS
Testing Method^a	AS Cases Detected^b,c	PWS Cases Detected^b
Methylation analysis	~80%	>99%
UBE3A molecular testing	~11%	None (n/a)
Cytogenetic testing	~68%	65-75%
Additional genetic testing	~10%	20-30%
^aTests are presented in the recommended order. ^bCertain cases may be detected via multiple testing methods, but not all methods will distinguish the mechanism of disease in detected cases; a combination of testing methods may be required. ^cApproximately 10% of AS cases result from currently unknown mechanisms and will not be detected. n/a, not applicable

Methylation Analysis

The initial and most sensitive test for AS and PWS is methylation analysis of 15q11.2-q13 using methods such as methylation-sensitive polymerase chain reaction (PCR) or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Methylation analysis confirms PWS in >99% of individuals with symptoms that meet consensus criteria and detects ~80% of AS cases.

Although methylation analysis does not always distinguish the causative mechanism of AS or PWS, MS-MLPA can be used to simultaneously assess methylation and copy number changes, thereby distinguishing between deletions that cause uniparental disomy and those that cause imprinting center defects.

UBE3A Molecular Testing

Testing for UBE3A variants is recommended for patients with AS if DNA methylation analysis fails to yield a diagnostic result, as approximately 11% of AS cases have been linked to pathogenic variants in the UBE3A gene. Sequencing should be performed first, followed by deletion/duplication analysis if sequencing fails to detect a pathogenic variant.

Cytogenetic Testing

Fluorescence in situ hybridization (FISH), typically performed with a karyotype, can be used in the evaluation of AS (if a pathogenic UBE3A variant is not identified) or PWS following methylation analysis to confirm deletions in 15q11.2-q13. FISH may also be used to detect chromosomal translocations or rearrangements with the appropriate probes. FISH should not be used alone because negative results do not exclude a diagnosis of AS or PWS.

Chromosomal microarray (CMA) will detect deletions in 15q11.2-q13, whereas cytogenetic single nucleotide polymorphism (SNP) microarray (CMA-SNP) will detect deletions and most cases of uniparental disomy due to deletion of the maternal or paternal critical region. However, CMA or CMA-SNP will not detect chromosomal translocations.

Additional Genetic Testing

If deletions or other abnormalities are not detected by the above techniques, DNA polymorphism testing (via PCR, MLPA, or gene-targeted microarray) of the patient and both parents can be used to distinguish between uniparental disomy and imprinting defects. DNA sequencing of the patient and both parents may also be useful to distinguish between imprinting center deletions and epimutations that lead to imprinting defects. Some cases of AS may present similarly to Rett syndrome or another MECP2-related disorder, which can be ruled out by molecular testing of the MECP2 gene.

Recurrence Risk Based on Mechanism in AS and PWS
Mechanism	Techniques for Detection	Cases	Recurrence Risk
15q11.2-q13 deletion	DNA methylation, MS-MLPA, FISH,^a CMA, CMA-SNP	AS: 65-75% PWS: 65-75%	<1%
Chromosomal translocation/rearrangement	FISH	AS: <1% PWS: <1%	≤50%
UPD (AS: paternal only; PWS: maternal only)	DNA methylation, MS-MLPA, CMA-SNP,^b DNA polymorphisms	AS: 2-7% PWS: 20-30%	<1%
UPD with predisposing parental translocation (AS: paternal only; PWS: maternal only)	DNA methylation, MS-MLPA, CMA-SNP,^b UPD study^c	AS: <1% PWS: <1%	≤100%
Imprinting defect with deletion in the IC	DNA methylation, MS-MLPA, DNA sequencing, AS IC deletion analysis^d	AS: 0.5% PWS: <0.5%	≤50%
Imprinting defect without deletion in the IC	DNA methylation, MS-MLPA, DNA polymorphisms	AS: 2.5% PWS: 2%	<1%
UBE3A pathogenic variant	Sequencing, deletion-duplication analysis	AS: 11% PWS: n/a	≤50%
Currently unknown	Unknown	AS: 10-15% PWS: n/a	Unknown
^aWith use of specific probes ^bDoes not detect all cases of UPD ^cDNA polymorphism testing using samples from patient and both parents ^dAnalysis via quantitative PCR, long-range PCR, MLPA, or gene-targeted microarray using samples from patient and both parents IC, imprinting center; UPD, uniparental disomy Sources: Dagli, 2017; Driscoll, 2017

Monitoring

Monitoring in Prader-Willi Syndrome

Insulinlike growth factor 1 (IGF-1) and growth hormone status testing is recommended to monitor the success of growth hormone treatment. Testing for hypothyroidism, including thyroid-stimulating hormone (TSH) and free thyroxine (T4), and testing for diabetes are recommended to monitor for comorbidities.

ARUP Lab Tests

Methylation Analysis

Preferred initial diagnostic test for AS or PWS

Angelman Syndrome and Prader-Willi Syndrome by Methylation-Sensitive PCR 2005077

Method: Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring

Prenatal testing for AS or PWS

Identify cases resulting from molecular mechanisms that produce abnormal methylation patterns

Angelman Syndrome and Prader-Willi Syndrome by Methylation-Sensitive PCR, Fetal 2012232

Method: Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring

UBE3A Test

Second-tier test for diagnosis of AS

Angelman Syndrome (UBE3A) Sequencing 2005564

Method: Polymerase Chain Reaction/Sequencing

Cytogenetic Tests

Follow-up test after methylation analysis in PWS and AS

Chromosome FISH, Metaphase 2002299

Method: Fluorescence in situ Hybridization

Cytogenomic SNP Microarray 2003414

Method: Genomic Microarray (Oligo-SNP Array)

Additional Genetic Tests

Screen for fetal microdeletions causing AS, PWS, and other syndromes

Non-Invasive Prenatal Testing for Fetal Aneuploidy with Microdeletions 2010232

Method: Targeted Sequencing with SNPs

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

Rett Syndrome (MECP2), Sequencing and Deletion/Duplication 0051614

Method: Sequencing/Multiplex Ligation-dependent Probe Amplification

Useful when a pathogenic familial variant identifiable by sequencing is known

Familial Mutation, Targeted Sequencing 2001961

Method: Polymerase Chain Reaction/Sequencing

Preferred test for screening and monitoring of thyroid function

Thyroid Stimulating Hormone 0070145

Method: Quantitative Chemiluminescent Immunoassay

Use in conjunction with TSH in cases of suspected secondary hypothyroidism

Thyroxine, Free (Free T4) 0070138

Method: Quantitative Electrochemiluminescent Immunoassay

Asses for diabetes mellitus or impaired glucose tolerance

Glucose Tolerance Test 0020542

Method: Quantitative Enzymatic

Assess growth hormone levels

Insulin-Like Growth Factor 1 (IGF-1) with Calculated Z-Score 2007698

Method: Quantitative Chemiluminescent Immunoassay

Growth Hormone 0070080

Method: Quantitative Chemiluminescent Immunoassay

Medical Experts

Coupal, Elena, MS, LCGC, Genetic Counselor, Molecular Genetics, at ARUP Laboratories

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

References

Dagli AI, Mueller J, Williams CA. Angelman Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, eds. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Updated: Dec 2017; Accessed: Jul 2019]
Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis E, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006; 140(5): 413-8. PubMed
Diagnostic testing for Prader-Willi and Angelman syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee. Am J Hum Genet. 1996; 58(5): 1085-8. PubMed
Driscoll D, Miller J, Schwartz S, Cassidy S. Prader-Willi Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last updated: Dec 2017; Accessed: Jul 2019]
Ramsden SC, Clayton-Smith J, Birch R, Buiting K. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Med Genet. 2010; 11: 70. PubMed
Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M, speakers contributors at the Second Expert Meeting of the Comprehensive Care of Patients with PWS. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008; 93(11): 4183-97. PubMed
Lossie AC, Whitney MM, Amidon D, Dong HJ, Chen P, Theriaque D, Hutson A, Nicholls RD, Zori RT, Williams CA, Driscoll DJ. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet. 2001; 38(12): 834-45. PubMed

Additional Resources

Buiting K. Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C Semin Med Genet. 2010; 154C(3): 365-76. PubMed

Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012; 14(1): 10-26. PubMed

Chen C, Visootsak J, Dills S, Graham JM. Prader-Willi syndrome: an update and review for the primary pediatrician. Clin Pediatr (Phila). 2007; 46(7): 580-91. PubMed

Kalsner L, Chamberlain SJ. Prader-Willi, Angelman, and 15q11-q13 duplication syndromes. Pediatr Clin North Am. 2015; 62(3): 587-606. PubMed

Shaffer LG, Agan N, Goldberg JD, Ledbetter DH, Longshore JW, Cassidy SB. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Genet Med. 2001; 3(3): 206-11. PubMed

Wattendorf DJ, Muenke M. Prader-Willi syndrome. Am Fam Physician. 2005; 72(5): 827-30. PubMed

Testing Algorithms

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Read more about Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Content Review:

July 2019

Last Update: August 2019

Angelman Syndrome and Prader-Willi Syndrome

Quick Answers

What are the symptoms of Angelman syndrome and Prader-Willi syndrome?

What are the genetic mechanisms that lead to Angelman syndrome or Prader-Willi syndrome, and why are they important to identify?

When is prenatal testing for Angelman syndrome or Prader-Willi syndrome appropriate?

Will laboratory testing diagnose all cases of Angelman syndrome?

Testing for Genetic Syndromes Related to Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder

Indications for Testing

Laboratory Testing

Diagnosis and Determination of Recurrence Risk

Methylation Analysis

UBE3A Molecular Testing

Cytogenetic Testing

Additional Genetic Testing

Monitoring

Monitoring in Prader-Willi Syndrome

ARUP Lab Tests

Diagnosis

Monitoring in PWS

Medical Experts

References

Additional Resources

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

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Angelman Syndrome and Prader-Willi Syndrome

Quick Answers

What are the symptoms of Angelman syndrome and Prader-Willi syndrome?

What are the genetic mechanisms that lead to Angelman syndrome or Prader-Willi syndrome, and why are they important to identify?

When is prenatal testing for Angelman syndrome or Prader-Willi syndrome appropriate?

Will laboratory testing diagnose all cases of Angelman syndrome?

Testing for Genetic Syndromes Related to Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder

Indications for Testing

Laboratory Testing

Diagnosis and Determination of Recurrence Risk

Methylation Analysis

UBE3A Molecular Testing

Cytogenetic Testing

Additional Genetic Testing

Monitoring

Monitoring in Prader-Willi Syndrome

ARUP Lab Tests

Diagnosis

Monitoring in PWS

Medical Experts

References

Additional Resources

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

ARUP Websites

ARUP Consult