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Prader-Willi Syndrome (PWS) by MS-MLPA

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Summary and Pricing

Test Method

Methylation-specific Multiplex Ligation-dependent Probe Amplification
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
2056 SNRPN 81331 81331 $540 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
2056SNRPN81331 81331 $540 Order Options and Pricing

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Greg Fischer, PhD

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

20 days on average for standard orders or 14 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Greg Fischer, PhD

Clinical Features and Genetics

Indications for Test

Indications for testing include confirmation of clinical diagnosis of PWS and reflex testing after a positive deletion test using CMA or FISH.

Clinical Features

Prader-Willi syndrome (PWS) is a multisystem disorder characterized by severe hypotonia, global developmental delay, feeding difficulties and failure to thrive in the newborn period, followed by hyperphagia (excessive eating) and development of morbid obesity in late infancy and early childhood. In addition, there is delay in the development of motor milestones and language, with all individuals showing some degree of cognitive impairment. Behavioral problems such as temper tantrums, stubbornness, manipulative behavior and obsessive-compulsive features are common in early childhood, and psychosis in adolescents and adults (Gunay-Aygun et al. 2001). Older male and female patients manifest hypogonadism (genital hypoplasia, incomplete pubertal development and infertility). Characteristic physical features include short stature, strabismus, almond-shaped palpebral fissures, narrow nasal bridge, thin upper lip with down-turned mouth, and scoliosis. Hypopigmentation of hair, eyes, and skin are seen in a third of the affected individuals. PWS has an estimated incidence of 1 in 15,000-25,000 live births.

Genetics

The PWS and related Angelman syndrome (AS) region is localized to a 5-6 Mb genomic region on the proximal long arm of chromosome 15 (15q11.2-q13). This region contains several genes that are differentially expressed depending on whether the region is inherited from the father or the mother, i.e., some genes in this regions are expressed only from the paternal chromosome and some expressed only from the maternal chromosome. This differential gene expression is achieved by differential methylation (imprinting) patterns on the paternal and maternal chromosomes. The PWS paternally-only expressed region contains five protein coding genes (MKRN3, MAGEL2, NDN, NPAP1, and SNURF-SNRPN), one ORF (C15orf2), and a family of small nucleolar RNA (snoRNA) genes. The AS maternally-only expressed region contains one gene, UBE3A. Deletion mapping in PWS/AS patients identified two small regions of deletion overlap (SRO) that define two critical imprinting centers (IC). PWS-SRO is a 4.3 kb region that lies at the 5’ end of the bicistronic SNURF-SNRPN, and has CpG islands encompassing the promoter, exon 1 and intron1 of SNURF-SNRPN. AS-SRO is 880bp in size and maps 35 kb proximal to the SNURF-SNRPN exon 1. The CpG islands are unmethylated in the expressed chromosomes and methylated in the unexpressed chromosomes (Cassidy et al. 2012).PWS is caused by loss of function of five coding genes on paternally inherited chromosome 15q11.2-q13. Loss of paternally expressed genes at 15q11.2-13 can arise from several different genetic mechanisms. Approximately 75-80% of the PWS patients have a recurrent deletion of the 15q11.2-13 on the paternally inherited chromosome, ~20-25% have a maternal uniparental disomy (UPD) of chromosome 15, < 5% have imprinting defect (ID) i.e., mutations within the imprinting control region that establishes a maternal methylation pattern on the paternal chromosome (approximately 10-15% of the PWS individuals with ID have a very small deletion in the PWS IC), and < 1% have a structural chromosome abnormality (e.g., translocation) involving 15q11.2-q13 .Absence or loss of expression of maternally expressed UBE3A gene leads to Angelman Syndrome.

Clinical Sensitivity - MS-MLPA

Approximately 99% of PWS cases will be detected by this assay. Because of simultaneous detection of both copy number and methylation status, MS-MLPA is able to differentiate between PWS caused by paternal deletion and those caused by maternal UPD or ID. If no deletion is present, DNA polymorphism analysis will be necessary to differentiate between maternal UPD and ID. However, MS-MLPA will pick up some IC deletions and deletions encompassing the SNORD116 gene cluster.

Testing Strategy

Methylation analysis (Nygren et al. 2005) of the PWS/AS IC is by far the most efficient starting point for a genetic diagnosis of PWS based on a clinical suspicion alone, as it can be used for all three classes of molecular defects (deletion, UPD and Imprinting defect). Additionally, methylation analysis differentiates between PWS and AS for patients with 15q11.2-q13 deletion without the need for the analysis of parental samples. Methylation analysis makes use of the differentially methylated maternal and paternal chromosome region at 15q11.2-q13.

At PreventionGenetics we use commercially available Methylation-specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) for the detection of PWS (Procter et al. 2006). This method combines both DNA methylation analysis and copy-number analysis across the entire PWS/AS region. MS-MLPA contains 32 dosage-sensitive probes (for copy number detection) specific for the 15q11.2 region, and five probes for determining the DNA methylation status at differentially methylated sites in 15q11.2. Additionally, the dosage-sensitive probes cover the SNORD116 (one of snoRNA gene clusters in PWS/AS region) gene cluster (Ramsden et al. 2010).

The advantages of MS-MLPA method include;

1) Combined detection of both copy-number and methylation status.
2) Can differentiate between PWS caused by paternal deletion or UPD/Imprinting defect.
3) Detection of methylation status at five distinct differentially methylated regions (instead of one locus).
4) Detection of small deletions encompassing IC and SNORD116 gene cluster.
5) Detects more than 99% of the PWS cases.

Indications for Test

Indications for testing include confirmation of clinical diagnosis of PWS and reflex testing after a positive deletion test using CMA or FISH.

Gene

Official Gene Symbol OMIM ID
SNRPN 182279
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Prader-Willi Syndrome 176270

Related Tests

Name
Angelman Syndrome by MS-MLPA
Angelman Syndrome via the UBE3A Gene

Citations

  • Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. 2012. Prader-Willi syndrome. Genet Med 14: 10–26 PubMed ID: 22237428
  • Gunay-Aygun M, Schwartz S, Heeger S, O’Riordan MA, Cassidy SB. 2001. The Changing Purpose of Prader-Willi Syndrome Clinical Diagnostic Criteria and Proposed Revised Criteria. Pediatrics 108: e92–e92. PubMed ID: 11694676
  • Nygren AOH, Ameziane N, Duarte HMB, Vijzelaar RNCP, Waisfisz Q, Hess CJ, Schouten JP, Errami A. 2005. Methylation-Specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res 33: e128. PubMed ID: 16106041
  • Procter M, Chou L-S, Tang W, Jama M, Mao R. 2006. Molecular Diagnosis of Prader–Willi and Angelman Syndromes by Methylation-Specific Melting Analysis and Methylation-Specific Multiplex Ligation-Dependent Probe Amplification. Clinical Chemistry 52: 1276–1283. PubMed ID: 16690734
  • Ramsden SC, Clayton-Smith J, Birch R, Buiting K. 2010. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Med Genet 11: 70. PubMed ID: 20459762

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

Specimen Types

Specimen Requirements and Shipping Details

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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