Prader-Willi/Angelman syndrome methylation testing1
Test #:
8750
Turnaround Time:
2-3 weeks
Specimen Requirements:
Specimens should be shipped at room temperature in a leak-proof, rigid container with overnight delivery. To discuss minimum acceptable specimens for neonatal patients or for sample types not listed, please contact Allele Diagnostics.
- Peripheral whole blood in EDTA: 2-3 mL
- Cord blood in EDTA: 2-3 mL
CPT Codes:
81331 x1
Ordering Requirements:
Condition Description:
Prader-Willi (PWS) syndrome is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of obesity (unless externally controlled). Motor milestones and language development are delayed. All individuals have some degree of intellectual disability. A distinctive behavioral phenotype (temper tantrums, stubbornness, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common; characteristic facial features, strabismus, and scoliosis may be present.
DNA methylation and deletion/duplication study of the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) Critical Region of chromosome 15. If the methylation pattern is characteristic of only maternal inheritance (absence of the paternally-inherited critical region), this is diagnostic for PWS. If the methylation pattern is characteristic of only paternal inheritance (absence of the maternally-inherited critical region), this is diagnostic for AS. This combined assay will provide information regarding the genetic mechanism by which an abnormal methylation result arises, e.g. by deletion vs. another mechanism such as uniparental disomy (UPD) or an imprinting defect. This assay does not distinguish between UPD and an imprinting defect.
In all patients with a clinical presentation of PWS, it is important to begin testing with methylation studies first. If abnormal, further testing such as FISH (70% of the causes), uniparental disomy (UPD) studies (30%) and sequencing of the imprinting center (<1%) may be considered.
PWS is caused by absence of the paternally derived PWS/AS region of chromosome 15 by one of several genetic mechanisms. The risk to the sibs of an affected child of having PWS depends upon the genetic mechanism that resulted in the absence of the paternally contributed PWS/AS region. The risk to sibs is less than 1% if the affected child has a deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control center, and up to 25% if a parental chromosomal translocation is present.
Clinical Utility:
- Confirmation of a clinical diagnosis of Angelman syndrome.
- Confirmation of a clinical diagnosis of Prader-Willi syndrome.
- This test is indicated for newborns with isolated, congenital hypotonia.
Test Description:
Methylation-specific assay of SNRPN and MAGEL2
Methylation-specific assay of the SNRPN and MAGEL2 alleles and deletion/duplication analysis of the 15q11.2-q13.1 loci, which contains the Prader-Willi/Angelman critical region (SALSA MLPA probemix ME028; MRC-Holland).Detection:
99% of cases of Prader-Willi detect and ~78% of cases of Angelman syndrome syndrome will be diagnosed by this method. 11% of individuals with a clinical diagnosis of Angelman syndrome will have a pathogenic variant in the UBE3A gene. UBE3A gene sequencing may be considered for individuals with a clinical diagnosis of Angelman syndrome but normal methylation studies.
This assay cannot provide detailed information regarding the size of a copy number change, but it can distinguish between type I (larger class, BP1-BP3) and type II (smaller class, BP2-BP3) copy number changes. Copy number variants that are limited to the BP1 to BP2 region of 15q11.2 are not reported.