Angelman Syndrome via the UBE3A Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
574 UBE3A$810.00 81406 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Approximately 10% of AS cases will exhibit causative mutations through sequencing (Sadikovic et al. 2014). Regulatory mutations, deep intronic mutations and large deletions and duplications cannot be detected by this method.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 UBE3A$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity
Less than 1% of the AS cases will be diagnosed by this assay.

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Clinical Features
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe developmental delay, intellectual disability, speech impairment, seizures and characteristic behavior with an inappropriate happy demeanor with easily provoked laughter, short attention span, smiling and excitability. Individuals with AS plateau at a developmental level of 24 to 30 months, and cognitive performance usually shows severe functional impairment. Most children with AS have reduced need for sleep, and frequent awakening at night is common (Lossie et al. 2001). Fifty percent of the children develop microcephaly (Occipital Frontal Circumference < 2SD) by the age of 12 months. All children with AS have some component of hyperactivity with seemingly ceaseless activity. Language impairment is severe with most individuals lacking speech entirely, but a few develop single-word vocabularies. A large subset of children with AS qualify for a comorbid diagnosis of autism. A subset of AS patients also have hypopigmentation of the skin, hair and eyes, attributable to haploinsufficiency of OCA2 gene (due to maternal deletion) located close to the UBE3A gene. The prevalence of AS is one in 12,000-20,000.

Differential diagnoses with several overlapping features with AS include Mowat-Wilson syndrome (Test  #1567), X-linked Christianson syndrome (Test  #562 and Test #600), Rett syndrome (Test #1455 and Test #600), Pitt-Hopkins syndrome (Tests #1523, #1522 and #600), 2q23.1 deletion syndrome (Test #1321), and Phelan-McDermid syndrome (Test #600).
The AS and related Prader-Willi syndrome (PWS) region is localized to a 5-6 Mb genomic region on the proximal long arm of chromosome 15 (15q11.2-q13). This region contains several genes that are differentially expressed depending on whether the region is inherited from the father or the mother, i.e., some genes in this regions are expressed only from the paternal chromosome and some expressed only from the maternal chromosome. This differential gene expression is achieved by differential methylation (imprinting) pattern on the paternal and maternal chromosomes. The PWS paternally-only expressed region contains five genes (MKRN3, MAGEL2, NDN, NPAP1, and SNURF-SNRPN), one ORF (C15orf2), and a family of small nucleolar RNA (snoRNA) genes or gene clusters. The AS maternally-only expressed region contains one gene, UBE3A. Deletion mapping in PWS/AS patients identified two small regions of deletion overlap (SRO) that define two critical imprinting centers (IC). PWS-SRO is a 4.3 kb region that lies at the 5’ end of the bicistronic SNURF-SNRPN, and has CpG islands encompassing the promoter, exon 1 and intron 1 of SNURF-SNRPN. AS-SRO is 880bp in size and maps 35 kb proximal to the SNURF-SNRPN exon 1.

AS is caused by loss of a functional UBE3A gene on maternally inherited chromosome 15q11.2-q13. Loss of this maternally expressed gene at 15q11.2-13 can arise from several different genetic mechanisms. Approximately 65-75% of AS patients have a recurrent deletion of 15q11.2-13 on the maternally inherited chromosome, ~3-7% have a paternal uniparental disomy (UPD) of chromosome 15, 3% have imprinting defect (ID) i.e., mutations within the imprinting control region that establish a paternal methylation pattern despite the presence of bi-parental chromosomes (approximately 10-15% of the AS individuals with ID have a very small deletion in the AS IC), and 5-10% of AS patients have mutations in the UBE3A gene (Williams et al. 2010; Dagli et al. 2012) .

Alternatively, absence or loss of expression of paternally expressed genes lead to PWS (Test #2056).

Sequence analysis of individuals with AS reveals that the majority of UBE3A mutations result in protein truncation. More than 60 causative mutations have been reported and 60-70% of these include small deletions and duplications leading to frame shift mutations. Approximately 25% include missense and nonsense mutations with the reminder includes splicing defects and gross deletions (Malzac et al. 1998). UBE3A encodes an E3 ubiquitin-protein ligase which is a component of the ubiquitin protein degradation system.
Testing Strategy
Methylation analysis of the PWS/AS IC is by far the most efficient starting point for a genetic diagnosis of AS based on a clinical suspicion alone, as it can be used for all three classes of molecular defects (deletion, UPD and Imprinting defect). This method should be the first test ordered on a clinical suspicion of AS (Test #2056).

Sanger sequencing of UBE3A should be considered for patients that fit the classic AS phenotype and have normal methylation analysis at the 15q11.2-q13 region.

A few individuals with AS have been found to have whole-gene, multi-exonic or intragenic deletions of the UBE3A gene (Boyes et al. 2006, Calì et al. 2010, Sato et al. 2007). A UBE3A deletion/duplication analysis via aCGH (Test  #600) should be considered for individuals with a normal methylation pattern and absence of UBE3A truncating mutations.
Indications for Test
Candidates for this test include: patients with a clinical diagnosis of AS, reflex testing after a normal UBE3A methylation analysis, and reflex testing after a positive deletion test using CMA or FISH.


Official Gene Symbol OMIM ID
UBE3A 601623
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Angelman Syndrome 105830

Related Tests

2q23.1 Microdeletion Syndrome and Autism Spectrum Disorder via the MBD5 Gene
Angelman Syndrome by MS-MLPA
Autosomal-Recessive Intellectual Disability via the NRXN1 Gene
Christianson Type X-Linked Mental Retardation via the SLC9A6 Gene
Cortical Dysplasia-Focal Epilepsy Syndrome via the CNTNAP2 Gene
Mowat-Wilson Syndrome via the ZEB2 Gene
Phelan-Mcdermid Syndrome, 22q13 Deletion Syndrome, or Autism Spectrum Disorder via the SHANK3 Gene
Prader-Willi Syndrome by MS-MLPA
Rett Syndrome via the MECP2 Gene


Genetic Counselors
  • Boyes L, Wallace AJ, Krajewska-Walasek M, Chrzanowska KH, Clayton-Smith J, Ramsden S. 2006. Detection of a deletion of exons 8–16 of the UBE3A gene in familial Angelman syndrome using a semi-quantitative dosage PCR based assay. European Journal of Medical Genetics 49: 472–480. PubMed ID: 16740422
  • Calì F, Ragalmuto A, Chiavetta V, Calabrese G, Fichera M, Vinci M, Ruggeri G, Schinocca P, Sturnio M, Romano S, Romano V, Elia M. 2010. Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome. Exp Mol Med 42: 842–848. PubMed ID: 21072004
  • Dagli A, Buiting K, Williams CA. 2012. Molecular and Clinical Aspects of Angelman Syndrome. Mol Syndromol 2: 100–112. PubMed ID: 22670133
  • Lossie A, Whitney M, Amidon D, Dong H, Chen P, Theriaque D, Hutson A, Nicholls R, Zori R, Williams C, Driscoll D. 2001. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 38: 834–845. PubMed ID: 11748306
  • Malzac P, Webber H, Moncla A, Graham JM, Kukolich M, Williams C, Pagon RA, Ramsdell LA, Kishino T, Wagstaff J. 1998. Mutation analysis of UBE3A in Angelman syndrome patients. Am J Hum Genet 62: 1353–1360. PubMed ID: 9585605
  • Sadikovic B, Fernandes P, Zhang VW, Ward PA, Miloslavskaya I, Rhead W, Rosenbaum R, Gin R, Roa B, Fang P. 2014. Mutation Update for UBE3A Variants in Angelman Syndrome. Hum. Mutat. 35: 1407–1417. PubMed ID: 25212744
  • Sato K, Iwakoshi M, Shimokawa O, Sakai H, Ohta T, Saitoh S, Miyake N, Niikawa N, Harada N, Saitsu H, Mizuguchi T, Matsumoto N. 2007. Angelman syndrome caused by an identical familial 1,487-kb deletion. Am. J. Med. Genet. 143A: 98–101. PubMed ID: 17152063
  • Williams CA, Driscoll DJ, Dagli AI. 2010. Clinical and genetic aspects of Angelman syndrome. Genet Med 12: 385–395. PubMed ID: 20445456
Order Kits

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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