Angelman Syndrome
Angelman Syndrome is caused by the loss of expression or function of the maternally inherited allele of the UBE3A gene. UBE3A disruption can occur through chromosomal deletion or rearrangement, point mutations in the gene, uniparental paternal disomy (UPD), or imprinting center mutations.
PrintAngelman Syndrome is caused by the loss of expression or function of the maternally inherited allele of the UBE3A gene. UBE3A disruption can occur through chromosomal deletion or rearrangement, point mutations in the gene, uniparental paternal disomy (UPD), or imprinting center mutations.
The majority of individuals acquire Angelman Syndrome through a non-inherited spontaneous event and the recurrence risk ranges from < 1% to 50% depending on the underlying genetic mechanism.
The Ambry SEQUENCE™: Angelman Syndrome test begins with methylation analysis of the SNRPN Gene, and if negative, reflexes to UBE3A gene sequence analysis. Methylation analysis of the SNRPN gene is capable of detecting deletions, UPD, and imprinting defects which cause >72% of Angelman Syndrome. Mutations detectable by UBE3A sequence analysis account for 10-11% of Angelman Syndrome. Therefore theAmbry SEQUENCE™ can detect over 82% of known defects causing Angelman Syndrome. Sequencing and methylation analysis are also offered individually.
Angelman syndrome (AS) is an autosomal dominant disorder characterized by severe developmental delay accompanied by severe speech impairment, gait ataxia or tremulousness of limbs, unique behavior that include a happy demeanor with frequent or inappropriate laughter, hyperactivity and social-seeking behavior. The prevalence of AS varies from one in 15,000-40,000.1,2 AS patients usually have normal prenatal history, fetal development, birth weight and head circumference at birth. Developmental delay starts at the age of six months, but symptoms specific to AS do not present until after one year of life. There is no cure for AS, but disease management is targeted to the prevention or control of seizures, behavior modifications, physical therapy and making the life of patients more comfortable. The life expectancy of individuals with AS is comparable to non-affected individuals.3,4
Angelman syndrome is caused by the loss of expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. UBE3A disruption can occur through one of the following genetic mechanisms: interstitial deletion on the maternal chromosome 15q11.2-q13 (~68-75%), point mutations in the UBE3A gene (~10-11%), uniparental paternal disomy (UPD, ~ 2-7%), an imprinting center (IC, 2-9%), or a cytogenetically visible chromosome rearrangement involving the 15q11.2-q13 region (~1%).4,5,6 The majority of individuals acquire AS through a non-inherited spontaneous event and recurrence risk ranges from <1% to 50% depending on the underlying genetic mechanism.7 AS is diagnosed using a combination of clinical features and molecular genetic testing, including methylation studies, FISH/aCGH analysis, and/or sequence analysis.
- Diagnostic testing is indicated for individuals known or suspected diagnosis of Angelman syndrome. Molecular testing to determine the underlying genetic mechanism can aid in accurate risk assessment.
- Maternal testing should be considered when a mutation in UBE3A has been identified in a proband to determine if the mutation is de novo or inherited for accurate risk assessment.
- Prenatal diagnosis may be considered in families with a previous history of Angelman syndrome.
The Ambry SEQUENCE: Angelman Syndrome, consist of two steps. Step 1 is methylation analysis of the SNRPN gene, and if negative, step 2 is reflex to UBE3A gene sequence analysis. Step 1and step 2 of the test are also offered individually. Methylation analysis of the SNRPN gene is performed by PCR to selectively amplify regions of gDNA corresponding to exon 1 and the putative promoter of the SNRPN gene followed by single-stranded sequencing on a pyrosequencing platform (Pyromark MD). Detecting the methylation pattern within the 15q11.2-13 locus allows for the discrimination between the maternal (methylated) and paternal (unmethylated) alleles. A total of 12 CpG dinucleotide sequences are analyzed for methylation status. UBE3A gene sequence analysis is performed by PCR-based doublestranded automated sequencing in the sense and antisense directions for exons 7-16 of the UBE3A gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. Specific mutation analysis for individual UBE3A mutations known to be in the family is also available.
Methylation analysis of the SNRPN gene is capable of detecting deletions, UPD and imprinting defects, which together cause >72% of Angelman syndrome. Gene sequence analysis of the UBE3A gene is capable of detecting >99% of described mutations in the UBE3A gene, which account for 10-11% of Angelman syndrome. The Ambry SEQUENCE, which combines methylation analysis and gene sequence analysis, can detect over 82% of known defects causing Angelman syndrome.
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 μg in TE at 50-100 ng/μl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.
| Test Code | Technique | CPT Codes |
|---|---|---|
| 2400 | UBE3A Gene Sequence Analysis | 83891x1, 83894x11, 83898x10, 83904x23, 83909x23, 83912x1 |
| 2420 | Angelman Syndrome, X-Linked SLC9A6 | 83891x1, 83894x16, 83898x15, 83904x28, 83909x28, 83912x1 |
| 8520 | Angelman Syndrome SNRPN and UBE3A | 83891x1, 83892x1, 83894x12, 83898x11, 83904x26, 83909x26, 83912x2 |
| 2440 | SNRPN Methylation | 83891x1, 83892x1, 83894x2, 83898x1, 83904x3, 83909x3, 83912x1 |
| Technique | Days |
|---|---|
| UBE3A Gene Sequence Analysis | 14-21 |
| 2420 Angelman Syndrome, X-Linked SLC9A6 | 14-21 |
| Angelman Syndrome SNRPN and UBE3A | 14-28 |
| SNRPN Methylation | 7-14 |
1 Stromme P. Dev Med Child Neurol. 2000; 42(2): 76-86.
2 Thomson AK et al. Disabil Rehabil. 2006; 28(5): 299-305.
3 Clayton-Smith J & Lann L. J Med Genet. 2003;40:87-95.
4 Van Buggenhout G & Fryns JP. Eur J Hum Genet advance online publication, 20 May 2009; doi:10.1038/ejhg.2009.67.
5 Williams CA et al. Angelman syndrome. 5 Sep 2008. GeneReviews, http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=angelman. Accessed August 24 2009.
6 Jiang Y et al. Am J Hum Genet. 1999;65:1-6.
7 Stalker HJ & Williams CA. Am J Med Genet. 1998;77(1):54-59.