ANGELMAN SYNDROME (AS)

Angelman syndrome (AS) is a disorder which involves moderate to severe mental retardation. AS patients also can have seizures, usually complete absence of speech, an ataxic jerky gait, hand-flapping, inappropriate laughter, protruding tongue and prognathism. The genetic basis of AS is heterogeneous making the diagnosis of this disorder difficult. Approximately 70% of cases are the result of a deletion in the maternally contributed 15q11-q13 chromosome. Approximately 3-5% of cases have received two copies of chromosome 15 from their father and none from their mother, termed paternal uniparental disomy (UPD). Like the deletion patients, the UPD patients are deficient for maternally derived genes on chromosome 15. Approximately 7-9% of cases have an abnormality in the imprinting process which causes nonexpression of maternal genes in the AS critical region. AS patients with the deficiencies listed above would exhibit abnormal DNA methylation patterns. Approximately 5% of AS patients carry a point mutation in the UBE3A gene. The other 10-14% of AS patients have a molecular etiology which is not determined and these cases should be referred to a research lab for further investigation. There are no consistent phenotypic differences between the patients with different molecular bases for their disease.

Reasons For Referral:

Confirmation of diagnosis or clinical suspicion of AS. The use of the methylation assay is not recommended for fetal samples since there is limited experience with methylation analyses of CVS and amniotic fluid samples and validation is required.

Testing Methodology:

Direct detection involves Southern blot analysis to identify the origin of mutation by detecting differences in methylation within the AS critical region using the methylation sensitive SNRPN probe. A paternal-only pattern is diagnostic for AS. For methylation positive AS cases, additional analyses including FISH and UPD studies may be considered to determine the mutational mechanism for genetic counseling purposes. A negative study does not rule out the diagnosis of AS since approximately 80% of patients are diagnosed with the methylation assay. AS patients who test negative by methylation studies may be candidates for UBE3A Sequence Analysis.

Specimen Requirements:

Blood: EDTA (purple-top) tubes: Adults: 14 cc; Child: 6 cc; Infant: 2-3 cc
Requisition form must accompany specimen. Prior to any genetic testing, we recommend genetic counseling and request that the subject, or their legal guardian, sign our consent form and submit it with the sample. To receive our forms and information about prenatal testing, please contact our laboratory.