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Interpretive Handbook

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Test 81153 :
Prader-Willi/Angelman Syndrome, Molecular Analysis

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.

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

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

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.

Clinical References 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


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