UBE3A Gene, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Angelman syndrome (AS) is characterized by significant developmental delay and mental retardation, ataxia, jerky arm movements, unprovoked laughter, seizures, and virtual absence of speech. AS has several known genetic causes.
About 65% to 80% of affected individuals have a de novo deletion of essentially the same region of chromosome 15 detected for Prader-Willi syndrome (PWS): 15q11.2-13. The deletion can often be identified by high-resolution chromosome analysis in conjunction with FISH analysis. Molecular testing has shown that the AS deletion occurs only on the copy of chromosome 15 inherited from the mother. In about 5% of patients with AS, the affected individuals have inherited 2 copies of chromosome 15 from their father (paternal uniparental disomy) and no copies of chromosome 15 from their mother. Thus, the individuals with AS resulting from deletion or uniparental disomy are deficient for maternally derived genes from chromosomes 15. Deletions and uniparental disomy occur as de novo events during conception, so the recurrence risk to siblings is very low. Both of these genetic alterations, along with imprinting center defects (accounting for another 2%-5% of AS cases), cause an abnormal methylation pattern in the PWS/AS region of chromosome 15.
Another 10% of patients with AS have a documented mutation in the UBE3A gene located in the PW/AS region on chromosome 15. Mutations can either be maternally inherited in an autosomal dominant fashion or de novo. If the mutation is inherited, the risk to all future pregnancies is 50%. If testing of the affected individual's mother confirms she does not carry the mutation, the risk to future pregnancies is low but not zero, as cases of germline mosaicism have been reported. Individuals with a UBE3A mutation will display a normal methylation patten.
No chromosomal or DNA abnormality has been identified in the remainder of clinically diagnosed AS patients (15%-25%). These patients may have genetic alterations that cannot be detected by current testing methods or alterations in as-yet unidentified genes.
Initial studies to rule-out AS should include high-resolution cytogenetic analysis (CMS/8696 Chromosome Analysis, for Congenital Disorders, Blood) to identify chromosome abnormalities that may have phenotypic overlap with AS, and methylation-sensitive, multiple ligation-dependent probe amplification (PWDNA/81153, Prader-Willi/Angelman Syndrome, Molecular Analysis) to identify deletions, duplications, and methylation defects. In cases where methylation analysis is negative, sequencing of the UBE3A gene may provide additional diagnostic information.
Determining if a UBE3A mutation identified in an affected individual is maternally inherited or de novo
Diagnostic confirmation of Angelman syndrome when a UBE3A mutation has been identified in an affected family member
Carrier screening of at-risk individuals when a UBE3A mutation has been identified in an affected family member
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
The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order UBEMS/89919 UBE3A Gene, Full Gene Analysis.
Analysis is performed for the familial mutations provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with Angelman syndrome.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to erroneous interpretation of results.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 for instructions for testing patients who have received a bone marrow transplant.
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. Lossie AC, Whitney MM, Amidon D, et al: Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 2001;38:834-845
2. Van Buggenhout G, Fryns JP: Angelman syndrome (AS, MIM 105830). Eur J Hum Genet 2009;17:1367-1373
3. Williams CA, Geaudet AL, Clayton-Smith J, et al: Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet 2006;140A:413-418