Test ID: PWDNA
Prader-Willi/Angelman Syndrome, Molecular Analysis
Secondary ID 
A test code used for billing and in test definitions created prior to November 2011
NY State Approved Indicates the status of NY State approval and if the test is orderable for NY State clients.
Useful For Suggests clinical disorders or settings where the test may be helpful
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/AS
Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request
Preferred first-tier test for diagnosis of Angelman and Prader-Willi syndromes. Multiplex ligation probe amplification (MLPA) is used to identify abnormal methylation of the PWS/AS region of chromosome 15.
Reflex Tests Lists test(s) that may or may not be performed, at an additional charge, depending on the result and interpretation of the initial test(s)
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| AFC | Amniotic Fluid Culture/Genetic Test | Yes | No |
| MCC | Maternal Cell Contamination, B | Yes | No |
Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.
For prenatal specimens only: If amniotic fluid (non-confluent 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.
Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test
Method Name A short description of the method used to perform the test
Methylation-Sensitive Multiple Ligation-Dependent Probe Amplification (MLPA)
(PCR is utilized pursuant to a license agreement with Roche Diagnostic Systems, Inc.)
Reporting Name A shorter/abbreviated version of the Published Name for a test; an abbreviated test name
Aliases Lists additional common names for a test, as an aid in searching
Methylation Studies
Prader-Willi Syndrome, Uniparental Disomy and Deletions
Specimen Type Describes the specimen type needed for testing
Specimen Required Defines the optimal specimen. This field describes the type of specimen required to perform the test and the preferred volume to complete testing. The volume allows automated processing, fastest throughput and, when indicated, repeat or reflex testing.
Mayo Medical Laboratories highly recommends that this test be ordered along with a routine chromosome analysis, CMS/8696 Chromosome Analysis, for Congenital Disorders, Blood, if the diagnosis of Prader-Willi syndrome or Angelman syndrome is not certain and chromosome analysis has not already been done.
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 (Supply T576) is available in Special Instructions.
2. Molecular Genetics-Congenital Inherited Diseases Patient Information Sheet (Supply T521) in Special Instructions
3. If not ordering electronically, submit a Molecular Genetics Request Form (Supply T245) with the specimen.
Specimen must arrive within 96 hours of collection.
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
Due to the complexity of prenatal testing, consultation with the laboratory is required for all prenatal testing. 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. All prenatal specimens must be accompanied by a maternal blood specimen. Order MCC/88636 Maternal Cell Contamination, Molecular Analysis on the maternal specimen.
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 Defines the amount of specimen required to perform an assay once, including instrument and container dead space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not sufficient) result, requiring a second specimen to be collected.
Reject Due To Identifies specimen types and conditions that may cause the specimen to be rejected
| Hemolysis | NA |
| Lipemia | NA |
| Icterus | NA |
| Other | NA |
Specimen Stability Information Provides a description of the temperatures required to transport a specimen to the laboratory. Alternate acceptable temperature(s) are also included.
| Specimen Type | Temperature | Time |
|---|---|---|
| Varies | Varies | |
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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% to 75%
-Maternal uniparental disomy (UPD): 20% to 30%
-Imprinting defect: 1% to 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% to 75%
-Paternal UPD: approximately 5%
-UBE3A mutation: approximately 10%
-Imprinting defect: 2% to 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 and/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 high-resolution cytogenetic 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 includes 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 additional information.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Interpretation Provides information to assist in interpretation of the test results
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
In addition to disease-related probes, the multiple ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Methylation status cannot be assessed on chorionic villus specimens.
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.
Rare cases of Prader-Willi syndrome or Angelman syndrome (AS) result from a subtle balanced translocation inherited from 1 of the parents. These may not be detected by this assay.
A negative molecular test result, especially in the case of a clinical suspicion of AS, does not rule out the diagnosis, because point mutations may not be detected by these methods
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
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
Method Description Describes how the test is performed and provides a method-specific reference
Methylation-sensitive multiple ligation-dependent probe amplification is utilized to test for the presence of large deletions, duplications and methylation defects in the Prader-Willi/Angelman syndrome critical region.(Unpublished Mayo method)
Day(s) and Time(s) Test Performed Outlines the days and times the test is performed. This field reflects the day and time the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time required before the test is performed. Some tests are listed as continuously performed, which means assays are performed several times during the day.
Monday, Wednesday
Analytic Time Defines the amount of time it takes the laboratory to setup and perform the test. This is defined in number of days. The shortest interval of time expressed is "same day/1 day," which means the results may be available the same day that the sample is received in the testing laboratory. One day means results are available 1 day after the sample is received in the laboratory.
Maximum Laboratory Time Defines the maximum time from specimen receipt at Mayo Medical Laboratories until the release of the test result
Specimen Retention Time Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded
Performing Laboratory Location The location of the laboratory that performs the test
Test Classification Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer's instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR), Investigation Use Only (IUO) product, or a Research Use Only (RUO) product.
CPT Code Information Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Medical Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
81331-SNRPN/UBE3A, (small nuclear ribonucleoprotein polypeptide Nand ubiquitin protein ligase E3A) (eg, Prader-Willi syndrome and/or Angelman syndrome), methylation analysis
LOINC® Code Information Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the result codes returned for this test or profile.
| Result ID | Reporting Name | LOINC Code |
|---|---|---|
| 16648 | Specimen | 31208-2 |
| 16649 | Specimen ID | N/A |
| 16650 | Source | N/A |
| 16651 | Order Date | N/A |
| 16652 | Reason For Referral | 42349-1 |
| 16653 | Method | In Process |
| 16654 | Result | 38907-2 |
| 16655 | Interpretation | 69047-9 |
| 16656 | Amendment | In Process |
| 16657 | Reviewed By: | N/A |
| 16658 | Release Date | N/A |
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