Referral Requirements

Important Note:

Diagnostic testing requires referral through Paediatrics, Neurology or Genetic Services.

Familial testing requires referral through Genetic Services.

Contacts:

Background Information

Angelman syndrome (AS) is characterised by severe developmental delay or mental retardation, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behaviour with an inappropriate happy demeanour that includes frequent laughing, smiling, and excitability. In addition, microcephaly and seizures are common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious.

AS is caused by the loss of the maternally imprinted contribution in the 15q11.2-q13 AS/Prader-Willi syndrome region that can occur by one of at least five different known genetic mechanisms. The risk to sibs of a proband depends on the genetic mechanism of the loss of the maternally contributed AS/PWS region: typically less than 1% for probands with a deletion or uniparental disomy (UPD); as high as 50% for probands with an imprinting defect mutation (ID) or a mutation of UBE3A. Members of the mother's extended family are also at increased risk when an ID or a UBE3A mutation is present.

Genetic testing identifies alterations in approximately 90% of individuals:

• Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with AS, including those with a deletion, UPD, or an imprinting defect.

• UBE3A sequence analysis detects mutations in an additional approximately 11% of individuals.

• Less than 1% of individuals have a cytogenetically visible chromosome rearrangement.

The remaining 10% of individuals with classic phenotypic features of AS have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing.

When the DNA methylation test is normal, UBE3A sequence analysis should be considered for individuals with clinical features of AS. The vast majority of UBE3A mutations result in (or predict) protein truncation without evidence of any hot spot location. It is possible that individuals with milder mutations (e.g., missense and mild promoter mutations) may show some, but not all, of the clinical features associated with AS. A few individuals with AS have been found to have complete or partial deletions of UBE3A, or to have intragenic deletions.

Methylation and UBE3A testing  is available.

For more information about the Molecular Genetics service:

Molecular Genetics information page