Clinical Information

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 pattern.

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 / 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 (PWAS / 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.