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Test ID: PWAS Prader-Willi/Angelman Syndrome, Molecular Analysis

Useful For

Confirmation of diagnosis in patients suspected of having either Prader-Willi syndrome (PWS) or Angelman syndrome (AS) based on clinical assessment or previous laboratory analysis

 

Prenatal diagnosis in families at risk for PWS or AS

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
CULAF Amniotic Fluid Culture/Genetic Test Yes No
MATCC Maternal Cell Contamination, B Yes No

Testing Algorithm

For prenatal specimens only: If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture/genetic test will be added and charged separately. For any prenatal specimen that is received, maternal cell contamination studies will be added.

 

See Prader-Willi and Angelman Syndromes: Laboratory Approach to Diagnosis in Special Instructions.

Method Name

Methylation-Sensitive Multiple Ligation-Dependent Probe Amplification (MLPA)
(PCR is utilized pursuant to a license agreement with Roche Diagnostic Systems, Inc.)

Reporting Name

Prader Willi/Angelman Mol Analysis

Specimen Type

Varies


Additional Testing Requirements


Mayo Medical Laboratories highly recommends that this test be ordered along with a routine chromosomal microarray analysis, CMACB / Chromosomal Microarray, Congenital, Blood, if the diagnosis of PWS or AS is not certain and chromosome analysis has not already been done.

 

All prenatal specimens must be accompanied by a maternal blood specimen. Order MATCC / Maternal Cell Contamination, Molecular Analysis on the maternal specimen.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.

 

Prenatal specimens can be sent Monday through Thursday and must be received by 5 p.m. CST on Friday in order to be processed appropriately.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Prenatal Specimens

Due to the complexity of prenatal testing, consultation with the laboratory is required for all prenatal testing.

 

Specimen Type: Amniotic fluid

Container/Tube: Amniotic fluid container

Specimen Volume: 20 mL

Specimen Stability Information: Refrigerated (preferred)/Ambient

 

Acceptable:

Specimen Type: Confluent cultured cells

Container/Tube: T-25 flask

Specimen Volume: 2 flasks

Collection Instructions: Submit confluent cultured cells from another laboratory.

Specimen Stability Information: Ambient (preferred)/Refrigerated


Specimen Minimum Volume

Blood: 1 mL
Amniotic Fluid: 10 mL

Specimen Stability Information

Specimen Type Temperature Time
Varies Varies

Clinical Information

Prader-Willi syndrome (PWS) is a congenital disorder characterized by a biphasic clinical course. Neonates with PWS are hypotonic, have a weak cry, and are poor feeders, but improve over time. In later infancy and childhood, individuals with PWS have global developmental delay, short stature, hypogonadism, small hands and feet, and marked hyperphagia leading to obesity. PWS is thought to be due to loss of function of paternally expressed genes, although specific genes have not yet been definitively implicated in the phenotype of PWS.

 

Etiology of Prader-Willi syndrome:

-Chromosome 15 deletion (15q11-13): approximately 70%-75%

-Maternal uniparental disomy (UPD): 20%-30%

-Imprinting defect: 1%-5%

-Chromosome rearrangement: rare

 

The phenotype caused by paternal deletions of 15q11-13 and by maternal UPD are generally identical with the exception of relative hypopigmentation being more common in patients with deletion PWS.

 

Angelman syndrome (AS) is a nonprogressive congenital disorder characterized by more significant developmental delay and mental retardation, ataxia, seizures, jerky arm movements, macrostomia, tongue thrusting, unprovoked laughter, brachycephaly, and virtual absence of speech. AS is due to loss of function of the maternally expressed gene UBE3A.

 

Etiology of Angelman syndrome:

-Chromosome 15 deletion (15q11-13): approximately 70%-75%

-Paternal UPD: approximately 5%

-UBE3A mutation: approximately 10%

-Imprinting defect: 2%-5%

-Chromosome rearrangement: rare

-Unknown: approximately 10%

 

The phenotype of AS patients with maternal deletions is generally more severe than that associated with paternal UPD or imprinting defects, including a higher rate or severity of microcephaly, seizures, and motor difficulties. Patients with AS caused by paternal UPD or imprinting defects generally show better growth and higher developmental and language abilities.

 

Both chromosome 15 deletions and UPD most often occur as de novo events during conception and, thus, recurrence risk to siblings is very low. In rare cases, chromosome 15 deletions and UPD occur as a result of parental translocations or other rare cytogenetic rearrangements, and in these cases recurrence risks to siblings are increased.

 

The recurrence risk associated with imprinting defects is dependent on whether or not there is an identifiable mutation.

 

UBE3A mutations can occur sporadically or be inherited in an autosomal dominant fashion. There is a 50% recurrence risk to siblings in cases of an inherited UBE3A mutation.

 

Due to the complex genetic etiology of PWS and AS and the corresponding variability in recurrence risks, careful cytogenetic and molecular testing and family assessment are necessary to provide accurate genetic counseling.

 

Initial studies to rule-out PWS or AS should include chromosomal microarray analysis to identify chromosome abnormalities that may have phenotypic overlap with PWS or AS, and methylation-sensitive multiple ligation-dependent probe amplification (MLPA) to identify deletions, duplications, and methylation defects. In cases where methylation-sensitive MLPA suggests either deletion or duplication, FISH can be used to confirm type I and type II deletions or characterize the disease mechanism, respectively. In cases where methylation-sensitive MLPA suggests abnormal methylation in the absence of a deletion or duplication, UPD studies can be used to characterize the disease mechanism.

 

Assessment of patients found to have a deletion in the PWS/AS critical region on routine cytogenetic analysis or chromosomal microarray can include confirmation of the deletion by FISH analysis and MLPA analysis to define parent of origin.

 

See Prader-Willi and Angelman Syndromes: Laboratory Approach to Diagnosis in Special Instructions for more information.

Reference Values

An interpretive report will be provided.

Interpretation

An interpretive report will be provided.

Clinical Reference

1. Buiting K: Prader-Willi syndrome and Angelman syndrome. Am J of Med Genet Part C 2010;154C:365-376

2. Williams CA, Beaudet AL, Clayton-Smith J, et al: Angelman syndrome 2005: updated consensus for diagnostic criteria. AM J Med Genet 2006:140A:413-418

3. Gunay-Aygun M, Schwartz S, Heeger S, et al: The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics 2001;108(5):e92

4. Nygren AOH, Ameziane N, Duarte HM, et al: Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res 2005;33:128

5. Procter M, Chou L, Tang W, et al: Molecular diagnosis of Prader-Willi and Angelman syndromes by methylation-specific multiplex ligation-dependent probe amplification. Clin Chem 2006;52:1276-1283

Day(s) and Time(s) Performed

Monday, Wednesday

Analytic Time

14 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81331-SNRPN/UBE3A, (small nuclear ribonucleoprotein polypeptide Nand ubiquitin protein ligase E3A) (eg, Prader-Willi syndrome and/or Angelman syndrome), methylation analysis

 

Amniotic Fluid Culture/Genetic Test

 

88235-Tissue culture for amniotic fluid (if appropriate)

 

88240-Cryopreservation (if appropriate)

Maternal Cell Contamination, B

 

81265-Comparative analysis using Short Tandem Repeat (STR) markers; patient and comparative specimen (eg, pre-transplant recipient and donor germline testing, post-transplant non-hematopoietic recipient germline [eg, buccal swab or other germline tissue sample] and donor testing, twin zygosity testing or maternal cell contamination of fetal cells (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
PWAS Prader Willi/Angelman Mol Analysis In Process

 

Result ID Test Result Name Result LOINC Value
52913 Result Summary 50397-9
52914 Result In Process
52915 Interpretation 69047-9
52916 Reason for Referral 42349-1
52917 Specimen 31208-2
52918 Source 31208-2
52919 Released By No LOINC Needed

Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521) in Special Instructions

3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

mml-inherited-molecular