Angelman Syndrome Tier 2 Panel - Clinical Genetic Test - GTR

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Angelman Syndrome Tier 2 Panel

Clinical Genetic Test

offered by

Genetic Services Laboratory

View lab's test page

GTR Test Accession: GTR000500158.6

INHERITED DISEASENERVOUS SYSTEMSYNDROMIC DISEASE ... View more

Last updated in GTR: 2020-08-10

Last annual review date for the lab: 2023-07-18

At a Glance

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; ...

Conditions (1):

Angelman syndrome

Genes (4):

MECP2 (Xq28), SLC9A6 (Xq26.3), TCF4 (18q21.2), UBE3A (15q11.2)

Methods (2):

Molecular Genetics - Deletion/duplication analysis: Next-Generation (NGS)/Massively parallel sequencing (MPS); ...

Target population:

Not provided

Clinical validity:

AS is caused by the absence or dysfunction of the …

Clinical utility:

Establish or confirm diagnosis

Ordering Information

Offered by:

Genetic Services Laboratory
View lab's website
View lab's test page

Specimen Source:

Amniocytes
Amniotic fluid
Buccal swab
Cell culture
Chorionic villi
Cord blood
Fetal blood
Fibroblasts
Fresh tissue
Frozen tissue
Peripheral (whole) blood
Product of conception (POC)
Saliva
View specimen requirements

Who can order:

Genetic Counselor
Health Care Provider
Licensed Physician
Nurse Practitioner
Physician Assistant
Registered Nurse

CPT codes:

**AMA CPT codes notice

Contact Policy:

Laboratory can only accept contact from health care providers. Patients/families are encouraged to discuss genetic testing options with their health care provider.

How to Order:

All samples should be shipped via overnight delivery at room temperature.

No weekend or holiday deliveries.

Label each specimen with the patient’s name, date of birth and date sample collected.

Send specimens with complete requisition and consent form, otherwise, specimen processing may be delayed.
Order URL

Test service:

Clinical Testing/Confirmation of Mutations Identified Previously
Confirmation of research findings

Test additional service:

Custom Prenatal Testing
Custom mutation-specific/Carrier testing

Test development:

Test developed by laboratory (no manufacturer test name)

Informed consent required:

Pre-test genetic counseling required:

Decline to answer

Post-test genetic counseling required:

Decline to answer

Recommended fields not provided:

Test Order Code, Lab contact for this test, Test strategy

Conditions

Total conditions: 1

Condition/Phenotype	Identifier

Test Targets

Genes

Total genes: 4

Gene	Associated Condition	Germline or Somatic	Allele (Lab-provided)	Variant in NCBI

Methodology

Total methods: 2

Method Category

Test method

Instrument *

Deletion/duplication analysis

Next-Generation (NGS)/Massively parallel sequencing (MPS)

Sequence analysis of the entire coding region

Bi-directional Sanger Sequence Analysis

* Instrument: Not provided

Clinical Information

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; Pre-symptomatic; Risk Assessment; Screening

Clinical validity:

AS is caused by the absence or dysfunction of the typically active maternal allele at chromosome 15q11-q13, while the clinically distinct Prader-Willi syndrome (PWS) is the result of dysfunction or absence of the paternal allele. The 15q11-q13 region contains several genes that are differentially methylated on maternally and paternally inherited … AS is caused by the absence or dysfunction of the typically active maternal allele at chromosome 15q11-q13, while the clinically distinct Prader-Willi syndrome (PWS) is the result of dysfunction or absence of the paternal allele. The 15q11-q13 region contains several genes that are differentially methylated on maternally and paternally inherited alleles. Within this region, the gene known to be active on the maternal allele is UBE3A [OMIM #601623], which encodes the E6AP-3A ubiquitin protein ligase. Ubiquitin molecules typically facilitate protein degradation. An absence/defect/lack of expression of the UBE3A gene is thought to be the basis of the large majority of AS. To date, AS is known to be caused by four different genetic mechanisms: • Deletions of 15q11-q13 on the maternally inherited chromosome (70-75% of cases). The majority of these cases are the result of large interstitial deletions, though cases involving translocations and smaller deletions have been noted. As a class, patients with AS caused by a deletion exhibit the most severe phenotype with the highest incidence of seizures (90%). Complete absence of speech and severe microcephaly is also typically seen in this group. • Paternal uniparental disomy (UPD) of chromosome 15 (2-5% of cases). These patients appear to be more mildly affected than those affected by a deletion. Patients with paternal UPD may have fewer severe seizures and less severe microcephaly; almost 50% can speak a few words. • Imprinting defects (2-5% of cases). Defects in the imprinting center (IC) at 15q11-q13 can change the methylation patterns and subsequent transcription activity of the genes within that region. Deletions of the IC region occur in 10-40% of patients with an IC defect and occur more frequently in familial cases. Epigenetic defects of the IC region are thought to comprise the remaining patients in this category and occur in sporadic cases. Patients in this group have a phenotype similar to those in the UPD group • UBE3A mutations (5-11% of cases). This mechanism should be considered for patients that fit the classic AS phenotype yet have normal methylation of chromosome 15. Up to 50% of all patients without molecular confirmation of the other mechanisms have a mutation in UBE3A, including 75-80% of all familial cases in this category. Most reported mutations are unique; the most frequently reported types of mutations are protein-truncating nonsense mutations. The phenotype of these patients has been described as intermediate between those of the deletion group and the UPD/IC defect group; seizure frequency, speech impairment, and severity of microcephaly is similar to what is noted in the deletion group, while ability to develop of motor skills and obesity is similar to that in the UPD/IC group. Male patients that have clinical features similar to AS that test negative for relevant AS genetic testing, may be considered for mutations in the SLC9A6 gene. SLC9A6 mutations have been identified in male patients with an Angelman-like syndrome phenotype who exhibit features such as developmental delay, mental retardation, seizures and a happy demeanor (X-linked Angelman-like syndrome). Other disorders that have several overlapping features with AS include Pitt-Hopkins syndrome (caused by mutations of the TCF4 gene) and atypical Rett syndrome (caused by mutations in the MECP2 gene). • De Pontual et al [2009] detected TCF4 mutations in 13 of 36 patients with severe psychomotor delay and facial features consistent with PHS, some of whom had previously been investigated for AS, Mowat-Wilson or Rett syndrome. • Watson et al [2001] detected MECP2 mutations in 5 out of 47 patients with a clinical diagnosis of AS. Testing for these disorders are available in our laboratory as part of the Angelman syndrome Tier 2 panel or separately. Details of these tests can also be found in our information sheets for X-linked Angelman-like syndrome, Pitt-Hopkins and Rett syndrome respectively (see website for pricing on separate tests). Additionally, about 10-15% of patients expressing the typical features of AS will have no currently discernable molecular defect. This may be the result of unidentified defects of the UBE3A gene, mutations in other genes in the ubiquitin pathway, or mutations in other genes. The phenotype in this group resembles the deletion group, with less frequent seizures. View more

View citations (9)

Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. Watson P, et al. J Med Genet. 2001;38(4):224-8. doi:10.1136/jmg.38.4.224. PMID: 11283202.
Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Lossie AC, et al. J Med Genet. 2001;38(12):834-45. doi:10.1136/jmg.38.12.834. PMID: 11748306.
Germline mosaicism of a novel UBE3A mutation in Angelman syndrome. Hosoki K, et al. Am J Med Genet A. 2005;138A(2):187-9. doi:10.1002/ajmg.a.30926. PMID: 16100729.
Angelman syndrome 2005: updated consensus for diagnostic criteria. Williams CA, et al. Am J Med Genet A. 2006;140(5):413-8. doi:10.1002/ajmg.a.31074. PMID: 16470747.
Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, Kroken M, Mattingsdal M, Egeland T, Stenmark H, Sjøholm H, Server A, Samuelsson L, Christianson A, Tarpey P, Whibley A, Stratton MR, Futreal PA, Teague J, Edkins S, Gecz J, Turner G, Raymond FL, Schwartz C, Stevenson RE, Undlien DE, Strømme P. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet. 2008;82(4):1003-10. doi:10.1016/j.ajhg.2008.01.013. Epub 2008 Mar 13. PMID: 18342287.
Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. de Pontual L, et al. Hum Mutat. 2009;30(4):669-76. doi:10.1002/humu.20935. PMID: 19235238.
Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Huibregtse JM, et al. Mol Cell Biol. 1993;13(2):775-84. doi:10.1128/mcb.13.2.775-784.1993. PMID: 8380895.
The spectrum of mutations in UBE3A causing Angelman syndrome. Fang P, et al. Hum Mol Genet. 1999;8(1):129-35. doi:10.1093/hmg/8.1.129. PMID: 9887341.
Williams C. “Angelman syndrome.” (2005). In: S. Cassidy and J. Allanson, eds. Management of Genetic Syndromes (2nd ed.). John Wiley & Sons. Hoboken, NJ.

Clinical utility:

Establish or confirm diagnosis

View citations (9)

Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. Watson P, et al. J Med Genet. 2001;38(4):224-8. doi:10.1136/jmg.38.4.224. PMID: 11283202.
Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Lossie AC, et al. J Med Genet. 2001;38(12):834-45. doi:10.1136/jmg.38.12.834. PMID: 11748306.
Germline mosaicism of a novel UBE3A mutation in Angelman syndrome. Hosoki K, et al. Am J Med Genet A. 2005;138A(2):187-9. doi:10.1002/ajmg.a.30926. PMID: 16100729.
Angelman syndrome 2005: updated consensus for diagnostic criteria. Williams CA, et al. Am J Med Genet A. 2006;140(5):413-8. doi:10.1002/ajmg.a.31074. PMID: 16470747.
Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, Kroken M, Mattingsdal M, Egeland T, Stenmark H, Sjøholm H, Server A, Samuelsson L, Christianson A, Tarpey P, Whibley A, Stratton MR, Futreal PA, Teague J, Edkins S, Gecz J, Turner G, Raymond FL, Schwartz C, Stevenson RE, Undlien DE, Strømme P. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet. 2008;82(4):1003-10. doi:10.1016/j.ajhg.2008.01.013. Epub 2008 Mar 13. PMID: 18342287.
Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. de Pontual L, et al. Hum Mutat. 2009;30(4):669-76. doi:10.1002/humu.20935. PMID: 19235238.
Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Huibregtse JM, et al. Mol Cell Biol. 1993;13(2):775-84. doi:10.1128/mcb.13.2.775-784.1993. PMID: 8380895.
The spectrum of mutations in UBE3A causing Angelman syndrome. Fang P, et al. Hum Mol Genet. 1999;8(1):129-35. doi:10.1093/hmg/8.1.129. PMID: 9887341.
Williams C. “Angelman syndrome.” (2005). In: S. Cassidy and J. Allanson, eds. Management of Genetic Syndromes (2nd ed.). John Wiley & Sons. Hoboken, NJ.

Variant Interpretation:

What is the protocol for interpreting a variation as a VUS?
Variants are identified and evaluated using a custom collection of bioinformatic tools and comprehensively interpreted by our team of directors and genetic counselors.

Will the lab re-contact the ordering physician if variant interpretation changes?
Yes.

Research:

Is research allowed on the sample after clinical testing is complete?
http://dnatesting.uchicago.edu/research-consent-form

Recommended fields not provided:

Target population, Are family members with defined clinical status recruited to assess significance of VUS without charge?, Sample negative report, Sample positive report

Technical Information

Availability:

Tests performed
Entire test performed in-house

Analytical Validity:

Analytical Sensitivity 99-100% Accuracy 100% Precision 100%

Assay limitations:

Only the coding and immediate flanking regions of the MECP2, TCF4, SLC9A6, and UBE3A genes were analyzed. Changes in the promoter region and other non-coding regions will not be detected by our assay. Our CNV detection algorithm was developed and its performance determined for the sole purpose of identifying deletions … View more

Proficiency testing (PT):

Is proficiency testing performed for this test?
Yes

Method used for proficiency testing:
Inter-Laboratory

VUS:

Software used to interpret novel variations
A custom collection of bioinformatics tools

Laboratory's policy on reporting novel variations
The laboratory reports novel variations.

Recommended fields not provided:

Test Confirmation, Citations to support assay limitations, Description of internal test validation method, Citations for Analytical validity, PT Provider, Description of PT method, Major CAP category, CAP category, CAP test list

Regulatory Approval

FDA Review:

Category: FDA exercises enforcement discretion

Additional Information

Reviews:

Genereviews

PubMed Clinical Queries

Clinical resources:

Molecular resources:

View SNRPN variations in ClinVar

View UBE3A variations in ClinVar

RefSeqGene

Coriell Institute for Medical Research

Practice guidelines:

Eurogentest, 2008

Consumer resources:

Genetic Alliance

MalaCards

MedlinePlusGenetics (GHR)

NCATS Office of Rare Diseases Research (GARD)

MedlinePlus

IMPORTANT NOTE: NIH does not independently verify information submitted to GTR; it relies on submitters to provide information that is accurate and not misleading. NIH makes no endorsements of tests or laboratories listed in GTR. GTR is not a substitute for medical advice. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.