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Angelman Syndrome via the UBE3A Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
UBE3A 81406 81406,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8321UBE3A81406 81406,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Greg Fischer, PhD

Clinical Features and Genetics

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.

Clinical Sensitivity - Sequencing with CNV PG-Select

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.

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

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). 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
Autosomal-Recessive Intellectual Disability via the NRXN1 Gene
Christianson Type X-Linked Mental Retardation via the SLC9A6 Gene
Mowat-Wilson Syndrome via the ZEB2 Gene
Phelan-Mcdermid Syndrome, 22q13 Deletion Syndrome, or Autism Spectrum Disorder via the SHANK3 Gene


  • 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 et al. 2012. PubMed ID: 22670133
  • Lossie et al. 2001. 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 et al. 2010. PubMed ID: 20445456


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

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