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SALSA MLPA Probemix ME028 Prader-Willi/Angelman

SALSA® MLPA® Probemix ME028 Prader-Willi/Angelman detects copy number variations and methylation status of the 15q11 region.

Specifications

Contents: 49 MLPA probes, including 36 for the 15q11-q13 region, of which 8 provide information on the methylation status.

Tissue: genomic DNA isolated from human peripheral whole blood or specified prenatal samples (see Intended Purpose).

Application: Prader-Willi syndrome (PWS), Angelman syndrome (AS), and 15q11 duplication syndrome.

CE-marked and registered for in vitro diagnostic (IVD) use in selected territories.

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Intended purpose

The SALSA MLPA Probemix ME028 Prader-Willi/Angelman is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative assay for the detection of copy number variations and methylation status of the 15q11 region in genomic DNA isolated from human peripheral whole blood specimens, or in case of extracted DNA from prenatal samples, from (1) (un)cultured amniotic fluid obtained in week 16 of the pregnancy or later and free from blood contamination, (2) (un)cultured chorionic villi free from maternal contamination (copy number only), (3) fetal blood. ME028 Prader-Willi/Angelman is intended to confirm a potential cause for and clinical diagnosis of Prader-Willi syndrome (PWS), Angelman syndrome (AS), and 15q11 duplication syndrome. In rare cases, this product can also be used for carrier testing of at-risk family members.

For the full intended purpose, see the product description.

Clinical background

Genomic imprinting is the monoallelic expression of genes, dependent on the parental origin of the chromosome. It plays a role in growth and development. Differentially methylated regions (DMRs) act as imprinting control regions to regulate the expression of imprinted genes. Imprinting disorders like Prader-Willi syndrome (PWS) and Angelman syndrome (AS) originate from a disturbance in this monoallelic expression by disruption or epimutation of imprinted genes (Ishida et al. 2013).

PWS and AS are distinct neurogenetic disorders, both usually caused by chromosomal deletions on chromosome 15q11 or by uniparental disomy (UPD). In UPD, both copies of a chromosome are inherited from a single parent. These 15q11 chromosomal alterations result in an aberrant expression profile of gene loci that are subject to imprinting. Absence of a paternal allele of chromosome 15q11, due to a chromosomal deletion of (part of) the paternal allele or the presence of two imprinted copies due to maternal UPD, results in PWS. The absence of the maternal copy of the same region or paternal UPD causes AS. Table 4 contains an overview of the expected copy number changes and methylation profiles in PWS/AS patients with deletions or aberrant methylation. Rare disorders with similar clinical features as PWS but different genetic etiology have been identified and are often referred to as PWS-like disorders. One of these PWS-like syndromes is caused by MAGEL2 truncating mutations and was renamed from PWS-like syndrome to Schaaf-Yang syndrome (OMIM #615547).

Paternally expressed genes in the 15q11 PWS/AS region are MKRN3, MAGEL2, NDN, SNRPN and the snoRNA cluster; while UBE3A is maternally expressed. The PWS-AS Imprinting Centre (IC) (located upstream of the SNURF-SNRPN gene) contains both the PWS-SRO (smallest region of deletion overlap) and the AS-SRO. The AS-SRO is required for the PWS/AS region to have the maternal pattern of epigenetic modification and gene expression only if the chromosome has an intact PWS-SRO. The PWS-SRO is a 4.1 kb region that includes the SNRPN promoter. The PWS-SRO is unconditionally required for the PWS/AS region to have the paternal pattern of epigenetic modification and gene expression.

Finally, a rare cause of PWS is a small deletion within the SNORD116 cluster, downstream of SNRPN (Sahoo et al. 2008). However, this deletion is only relevant when it is absent in parental samples. Additional probes for the 15q11 region are present in the SALSA MLPA Probemix P343 Autism-1 and the SALSA MLPA Probemix P336 UBE3A, please note that these are research use only (RUO) assays.

Additionally, maternal duplications of the PWS/AS critical region on 15q11.2-q13.1 cause the 15q11 duplication syndrome characterized by developmental delay, intellectual disability, hypotonia, and seizures. The extra copy is most commonly a maternal isodicentric 15q11.2-q13.1 supernumerary chromosome (80% of cases) or a maternal interstitial 15q11.2-q13.1 duplication (20% of cases).

The database of genomic variants mentions that copy number changes in the breakpoint region BP1-BP2 (NIPA1 and TUBGCP5) and u1B-u1B (SNRPN exons 1 and 2) region have been found in healthy individuals (see http://dgv.tcag.ca/dgv/app/home). According to Stefansson et al. (2008), a deletion of the BP1-BP2 region is present in 0.19% of normal individuals and in 0.55% of schizophrenia patients. More probes for this BP1-BP2 region can be found in the SALSA MLPA Probemix P211 HSP region (RUO).

More information is available at:

Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes | European Journal of Human Genetics (nature.com)

https://www.ncbi.nlm.nih.gov/books/NBK1330/ (PWS),

https://www.ncbi.nlm.nih.gov/books/NBK1144/ (AS), and

https://www.ncbi.nlm.nih.gov/books/NBK367946/ (15q11 Duplication Syndrome).

Regulatory status

SALSA MLPA Probemix ME028 Prader-Willi/Angelman is CE-marked for in vitro diagnostic (IVD) use. This assay has also been registered for IVD use in Colombia.

This assay is for research use only (RUO) in all other territories.

Product documentation

Version D1

Other versions

Contact us for earlier versions.

List prices

Product

Item no.
Description
Technology
Price
ME028-025R
SALSA MLPA Probemix ME028 Prader-Willi/Angelman – 25 rxn
MS-MLPA
€ 281.00
ME028-050R
SALSA MLPA Probemix ME028 Prader-Willi/Angelman – 50 rxn
MS-MLPA
€ 550.00
ME028-100R
SALSA MLPA Probemix ME028 Prader-Willi/Angelman – 100 rxn
MS-MLPA
€ 1075.00

Required reagents

A general SALSA MLPA Reagent Kit and SALSA HhaI are required for MS-MLPA experiments (to be ordered separately).

Item no.
Description
Technology
Price
EK1-FAM
SALSA MLPA Reagent Kit – 100 rxn – FAM (6 vials)
MLPA MS-MLPA
€ 341.00
EK1-Cy5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
MLPA MS-MLPA
€ 341.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 1571.00
EK5-Cy5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
MLPA MS-MLPA
€ 1571.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 6037.00
SMR50
SALSA HhaI – 115 μl
MS-MLPA
€ 45.00

Other products

These optional accessories can be ordered separately.

Item no.
Description
Technology
Price
PCR001-FAM
SALSA PCR Reagents – 100 rxn – FAM
MS-MLPA
€ 169.50
PCR003-FAM
SALSA PCR Reagents – 300 rxn – FAM
MS-MLPA
€ 465.50
How to Order

Positive samples

Inclusion of a positive sample is usually not required, but can be useful for the analysis of your experiments. MRC Holland has very limited access to positive samples and cannot supply such samples. We recommend using positive samples from your own collection. Alternatively, you can use positive samples from an online biorepository, such as the Coriell Institute.

The commercially available positive samples below have been tested with the current (D1) version of this product and have been shown to produce useful results.

  • Coriell NA13554: Heterozygous deletion (maternal) affecting the probes for SNRPN exon 3 and exon u5; asymptomatic.
  • Coriell NA13556: Heterozygous deletion (paternal) affecting the probes for SNRPN exon 3 and exon u5; Prader-Willi syndrome.
  • Coriell NA20375: Heterozygous deletion affecting the probes for MKRN3, MAGEL2, NDN, SNRPN, UBE3A, ATP10A, GABRB3 and OCA2; Angelman syndrome.
  • Coriell NA20408: Uniparental disomy (no copy number changes); Prader-Willi syndrome.
  • Coriell NA21887: Heterozygous deletion affecting the probes for TUBGCP5, NIPA1, MKRN3, MAGEL2, NDN, SNRPN, UBE3A, ATP10A, GABRB3 and OCA2; Angelman syndrome.
  • Coriell NA22397: Heterozygous duplication (maternal) affecting the probes for MKRN3, MAGEL2, NDN, SNRPN, UBE3A, ATP10A, GABRB3 and OCA2.
  • NIBSC Institute: The NIBSC Institute provides an excellent panel of WHO certified genomic DNA samples for Prader Willi and Angelman syndrome (catalogue number 09/140).

Resources

General resources

Learning

Publications

Selected publications using SALSA MLPA Probemix ME028 Prader-Willi/Angelman

  • Aypar U et al. (2014). Does parent of origin matter? Methylation studies should be performed on patients with multiple copies of the Prader-Willi/Angelman syndrome critical region. Am J Med Genet A. 164A:2514-20.
  • Dawson AJ et al. (2015). PWS/AS MS-MLPA Confirms Maternal Origin of 15q11.2 Microduplication. Case Rep Genet. 2015:474097.
  • Grootjen LN et al. (2022). Atypical 15q11.2-q13 Deletions and the Prader-Willi Phenotype. J Clin Med. 11:4636.
  • Kim B et al. (2022). Clinical Utility of Methylation-Specific Multiplex Ligation-Dependent Probe Amplification for the Diagnosis of Prader-Willi Syndrome and Angelman Syndrome. Ann Lab Med. 42:79-88.
  • Lu W et al. (2014). Clinical and genetic features of Prader-Willi syndrome in China. Eur J Pediatr. 173:81-6.
  • Luk HM et al. (2018). The Clinical and Molecular Spectrum of 15q Duplication Syndrome in Chinese. HK J Paediatr. 23:173-8.
  • Piard J et al. (2011). Intragenic deletion of UBE3A gene in 2 sisters with Angelman syndrome detected by MLPA. Am J Med Genet A. 155A:3170-3.
  • Prapasrat C et al. (2022). The Utilization of MS-MLPA as the First-Line Test for the Diagnosis of Prader-Willi Syndrome in Thai Patients. J Pediatr Genet. 12:273-9.
  • Ramsden SC et al. (2010). Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Med Genet. 11:70.
  • Zhang L et al. (2022). Genetic subtypes and phenotypic characteristics of 110 patients with Prader-Willi syndrome. Ital J Pediatr. 48:121.

References

  • Ishida M et al. (2013). The role of imprinted genes in humans. Mol Aspects Med. 34:826-40.
  • Sahoo T et al. (2008). Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet. 40:719-21.
  • Stefansson H et al. (2008). Large recurrent microdeletions associated with schizophrenia. Nature. 455:232-6.
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CE

CE-marked products are for In Vitro Diagnostic (IVD) use only in EU (candidate) member states and members of the European Free Trade Association (EFTA), and the UK.

CO

IVD-registered in Colombia.