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P044 NF2

SALSA® MLPA® Probemix P044 NF2 detects copy number variations in the NF2 gene.

Specifications

Contents: 43 MLPA probes, including 21 probes for NF2, 5 probes for genes upstream of NF2 , and 4 probes for genes downstream of NF2.

Tissue: genomic DNA isolated from human peripheral whole blood. Research use: genomic DNA from FFPE or fresh tumour tissue.

Application: NF2-related schwannomatosis.

IVDD certified for in vitro diagnostic (IVD) use.

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The format of the product description has recently been updated. Some information can now be found in a different location (more information).

Intended purpose

The SALSA MLPA Probemix P044 NF2 is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative manual assay for the detection of deletions or duplications in the NF2 gene in genomic DNA isolated from human peripheral whole blood specimens. P044 NF2 is intended to confirm a potential cause for and clinical diagnosis of NF2-related schwannomatosis and for molecular genetic testing of at-risk family members. NF2-related schwannomatosis has a high incidence of mosaicism (~15% of patients are mosaic) and mosaic mutations may not be detectable in blood.

For the full intended purpose, see the product description.

Clinical background

NF2-related schwannomatosis (formerly known as Neurofibromatosis type 2) is an autosomal dominant cancer susceptibility/predisposition syndrome that is characterized by the development of bilateral vestibular schwannomas (BVSs) in almost all patients. This disease is caused by inactivating mutations of the neurofibromatosis type 2 (NF2) tumour-suppressor gene. BVSs result in hearing loss, tinnitus and balance dysfunction. The age of onset is between 18 and 24 years. Patients also suffer from schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and rarely, astrocytomas. Although most of these tumours are not malignant, their anatomic location and multiplicity lead to high morbidity and mortality at a low age: the average age of death is 36 years. NF2-related schwannomatosis occurs in approximately 1 in 25,000-40,000 live births and the estimated prevalence in the general population is 1 in 50,000 without any known ethnic or racial bias. For known pathogenic mutations the penetrance is close to 100% (Asthagiri et al. 2009).

Mutational analysis of the NF2 gene in typical NF2-related schwannomatosis patients has demonstrated causative mutations in ~70%. The NF2 gene behaves as a typical tumour-suppressor gene, with first hits detectable in both constitutional and tumour specimens and second hits detectable only in tumours. Approximately 50% of NF2 mutation-positive patients inherit a germline mutation from an affected parent and the remaining half are sporadic cases due to de novo mutations. Large alterations affecting the NF2 gene account for 15-20% of all known NF2 mutations (Abo-Dalo et al. 2010; Halliday et al. 2017; Kluwe et al. 2005; Smith et al. 2016). Combined with the 70% NF2 mutation detection rate in patients, this means that in 10-15% of NF2-related schwannomatosis patients large deletions or duplications are detected. A high level of mosaicism is observed in NF2-related schwannomatosis, which can complicate mutation detection. More than 30% of the de novo cases are mosaic for NF2 mutations, which may result in subclinical symptoms and/or difficulties with mutation detection, resulting in a false negative diagnosis (Evans et al. 2007).

Mutations in NF2 are also frequently found in sporadic schwannomas and meningiomas (Lassaletta et al. 2013; Mohyuddin et al. 2002; Pathmanaban et al. 2017). Both NF2-related schwannomatosis syndromic tumours and such sporadic tumours have often lost a large part of chromosome 22 resulting in loss of heterozygosity (LOH) of NF2. These large chromosomal deletions frequently include loss of SMARCB1 and LZTR1, which are also recognized as tumour suppressor genes associated with schwannomatosis.

More information on NF2-related schwannomatosis can be found at https://www.ncbi.nlm.nih.gov/books/NBK1201/ and https://omim.org/entry/101000/.

Regulatory status

SALSA MLPA Probemix P044 NF2 is CE-marked under the IVDD for in vitro diagnostic (IVD) use in Europe.

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

Product documentation

Version C1

Other versions

Contact us for earlier versions.

List prices

Product

Item no.
Description
Technology
Price
P044-025R
SALSA MLPA Probemix P044 NF2 – 25 rxn
MLPA
€ 286.00
P044-050R
SALSA MLPA Probemix P044 NF2 – 50 rxn
MLPA
€ 560.00
P044-100R
SALSA MLPA Probemix P044 NF2 – 100 rxn
MLPA
€ 1096.00

Required reagents

A general SALSA MLPA Reagent Kit is required for 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
€ 348.00
EK1-Cy5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
MLPA MS-MLPA
€ 348.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 1600.00
EK5-Cy5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
MLPA MS-MLPA
€ 1600.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 6152.00

Price details & ordering

The prices above are list prices for direct orders from MRC Holland. Contact us for a quote that takes discounts and additional costs (such as shipping costs) into account. Different prices apply for orders through one of our sales partners; contact your local supplier for a quote.

More information about ordering & prices

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 (C1) version of this product and have been shown to produce useful results.

  • Coriell NA07106: Heterozygous duplication affecting all NF2 probes. The flanking probes are also affected.

Resources

General MLPA resources

MLPA education

Publications

Selected publications using P044 NF2

  • Chen H et al. (2018). Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressors. EBioMedicine. 36:252-65.
  • Evans DG et al. (2018). Schwannomatosis: a genetic and epidemiological study. J Neurol Neurosurg Psychiatry. 89:1215-9.
  • Evans DG et al. (2019). Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing. Genet Med. 21:1525-33.
  • Evans DG et al. (2019). Familial unilateral vestibular schwannoma is rarely caused by inherited variants in the NF2 gene. Laryngoscope. 129:967-73.
  • Evans DG et al. (2020). Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing. Genet Med. 22:53-9.
  • Forde C et al. (2021). Disease course of neurofibromatosis type 2: a 30-year follow-up study of 353 patients seen at a single institution. Neuro Oncol. 23:1113-24.
  • Forde C et al. (2024). NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study. J Med Genet. 61:856-60.
  • Kluwe L et al. (2005). Screening for large mutations of the NF2 gene. Genes Chromosomes Cancer. 42:384-91.
  • Pasmant E et al. (2018). Neurofibromatosis type 2 French cohort analysis using a comprehensive NF2 molecular diagnostic strategy. Neurochirurgie. 64:335-41.
  • Smith MJ et al. (2016). The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes. Hum Mutat. 37:250-6.

References

  • Abo-Dalo B et al. (2010). Large intragenic deletions of the NF2 gene: breakpoints and associated phenotypes. Genes Chromosomes Cancer. 49:171-5.
  • Asthagiri AR et al. (2009). Neurofibromatosis type 2. Lancet. 373:1974-86.
  • Evans DGR et al. (2007). Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet. 44:424-8.
  • Halliday D et al. (2017). Genetic Severity Score predicts clinical phenotype in NF2. J Med Genet. 54:657-64.
  • Kluwe L et al. (2005). Screening for large mutations of the NF2 gene. Genes Chromosomes Cancer. 42:384-91.
  • Lassaletta L et al. (2013). NF2 genetic alterations in sporadic vestibular schwannomas: clinical implications. Otol Neurotol. 34:1355-61.
  • Mohyuddin A et al. (2002). Molecular genetic analysis of the NF2 gene in young patients with unilateral vestibular schwannomas. J Med Genet. 39:315-22.
  • Pathmanaban ON et al. (2017). Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults. JAMA Neurol. 74:1123-9.
  • Smith MJ et al. (2016). The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes. Hum Mutat. 37:250-6.
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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.