Diagnostic Test Directory

Molecular Genetics Laboratory

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Angelman Syndrome (UBE3A Sequence Analysis)

  • LIS Mnemonic: MBUBE3AFSCR

    Collect

    Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.

    Volume Required

    5 ml whole blood or 4 ug DNA.

    Minimum Required

    3 ml whole blood

    Transport

    Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.

    Stability

    Whole blood can be refrigerated until shipment.

    Unacceptable conditions

    Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

    Specimen Handling

    Do not heat, freeze or centrifuge blood before shipment. Refrigerate sample until shipment.

Days Performed

Mon - Fri 9:00am to 4:00pm

Reported

4-6 weeks

CPT

81406

Disease Information

Clinical Features:

Angelman syndrome (AS) is a neurobehavioral disorder with an incidence of 1 in 20,000 Angelman syndrome (AS) is characterized by severe developmental delay or mental retardation, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriately happy demeanor that includes frequent laughing, smiling, and excitability. In addition, microcephaly and seizures are common.

Molecular Genetics:

Angelman syndrome is caused by the absence of the maternally derived region (15q11-15q13) on chromosome 15. The disorder is genetically heterogeneous. Approximately 70% of patients have a large deletion on maternal chromosome 15q11-q13; 1% of patients have rarer structural chromosome anomalies; about 7% of patients have paternal uni-parental disomy (UPD) for chromosome 15; 3% of patients carry an Imprinting Centre (IC) mutation; and 11 % have a UBE3A gene mutation. Most of the mutations identified in the UBE3A gene are truncating or frameshift mutations in the Hect domain of the protein. Missense mutations outside the hect domain are related to a milder phenotype. About 10% of AS patients have no detectable mutation.

Test Methods:

Methylation sensitive PCR is performed using primers specific for the methylated (maternal) and unmethylated (paternal) alleles of the SNRPN gene. In unaffected individuals, biparental inheritance is demonstrated by the presence of both maternal and paternal products. In a child affected with Angleman syndrome, only the paternal allele is observed. We also offer DNA sequence analysis of the entire coding region of the UBE3A gene (exons 7-16) including splice junctions. PCR amplification and sequencing is performed on all coding exons. The patient’s gene sequence is then compared to a reference sequence. Sequence variants are classified as mutations, variants of unknown significance or benign variants unrelated to disease. Variants of unknown significance may warrant further studies in the patient and other family members.

Detection Rate:

Methylation studies would diagnose ~80% of patients with Angelman syndrome (including deletions, uniparental disomy, and imprinting center mutations). Sequence analysis of the UBE3A gene would diagnose an additional ~11% of affected patients.

Related Tests:

Known point mutation analysis is available to family members for previously identified mutations in the UBE3A gene. Prenatal Testing is available to individuals who are confirmed carriers of point mutations in the UBE3A gene. Please contact the laboratory director to discuss appropriate testing prior to collecting a prenatal specimen. X-linked Angelman-like Syndrome: SLC9A6 Sequence Analysis

Results:

Test results with interpretation will be mailed and/or faxed to the referring physician or send out lab following completion of the test. Additional reports will be provided as requested.

Utility:

The clinical utility of these assays is to confirm a clinical diagnosis; facilitate proper clinical management, and to alert parents to possible recurrence risk.

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215-590-5221