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  • Test code: 04167
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
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Invitae Neurofibromatosis Type 2 Test

Test description

This test analyzes the NF2 gene, which is associated with neurofibromatosis type 2 (NF2), a condition predisposing affected individuals to the development of benign central nervous system tumors including vestibular schwannomas, meningiomas, ependymomas, and, very rarely, astrocytomas.

This test can also distinguish schwannomatosis from NF2 prior to the development of vestibular schwannomas. In NF2, vestibular schwannomas usually develop by age 30 and are a hallmark of the disease; in schwannomatosis, vestibular schwannomas are absent. Medical management, natural history, treatment, mortality, and genetic risks differ greatly between schwannomatosis and NF2, so distinguishing the two phenotypes is of critical importance.

Genetic testing may establish or confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also encourage testing and diagnosis of at-risk relatives.

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Primary panel (1 gene)
Add-on Schwannomatosis Gene (1 gene)

Prior to the development of vestibular schwannomas, NF2 can be difficult to distinguish from schwannomatosis. The development of vestibular schwannomas, usually by age 30, is a hallmark of NF2, whereas in schwannomatosis, vestibular schwannomas are absent. This gene can be added for no additional charge.

SMARCB1

  • neurofibromatosis type 2 (NF2)

Neurofibromatosis type 2 (NF2) is a hereditary disorder characterized by the growth of non-cancerous tumors in the central nervous system. The most common tumors are vestibular schwannomas (also known as acoustic neuromas) that form along the auditory nerve (eighth cranial nerve) and that are typically bilateral. Symptoms include hearing loss, tinnitus, and balance problems; the average age of onset is between 18 and 24 years of age.

Tumor typeLifetime risk
Bilateral vestibular schwannoma ~100%
Meningioma 50%-80%
Intramedullary tumors of the spinal cord 5%-33%
Spinal schwannoma Up to 66%

A recognized feature of NF2 is a childhood-onset mononeuropathy, often presenting with facial palsy, squint as a result of third nerve palsy, or a foot or hand drop. There additionally appears to be a progressive polyneuropathy of adulthood.

Affected individuals may also develop schwannomas of other cranial and peripheral nerves, including meningiomas, ependymomas, and, very rarely, astrocytomas. Skin tumors are common and are typically asymptomatic schwannomas. Posterior subcapsular lens opacities are the most common ocular findings and may be the first sign of NF2 in childhood; these may potentially progress to cataract.

Mutations in the NF2 gene occur in greater than 92% of familial cases and in approximately 70% of simplex cases (i.e., a single occurrence in a family) of NF2.

Autosomal dominant. Approximately 50% of cases are inherited from an affected parent and 50% are the result of a spontaneous de novo mutation. In 25%-30% of apparently sporadic cases, the affected individual has constitutional mosaicism for an NF2 pathogenic variant.

The prevalence of NF2 is estimated at 1 in 33,000 individuals.

Analysis of the NF2 gene may be considered in individuals with a personal and/or family history of the following:

  • unilateral or bilateral vestibular schwannomas
  • neurofibromas
  • gliomas
  • multiple meningiomas
  • posterior posterior subcapsular lenticular opacities
  • cataract

Clinical diagnostic criteria for NF2 have been proposed by the National Institutes of Health Consensus Development Conference:


with a revised version suggested by:

  1. Evans, DG, et al. 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. 2007; 44(7):424-8. doi: 10.1136/jmg.2006.047753. PMID: 17307835
  2. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch. Neurol. 1988; 45(5):575-8. doi: 10.1016/s0002-8177(88)73025-1. PMID: 3128965
  3. Wallace, AJ, et al. Mutation scanning of the NF2 gene: an improved service based on meta-PCR/sequencing, dosage analysis, and loss of heterozygosity analysis. Genet. Test. 2004; 8(4):368-80. doi: 10.1089/gte.2004.8.368. PMID: 15684865
  4. Evans, DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009; 4:16. doi: 10.1186/1750-1172-4-16. PMID: 19545378
  5. Evans, DG. Neurofibromatosis 2. 1998 Oct 14. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1201/ PMID: 20301380
  6. Baser, ME, et al. Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genet. Med. 2011; 13(6):576-81. doi: 10.1097/GIM.0b013e318211faa9. PMID: 21451418
  7. Lloyd, SK, Evans, DG. Neurofibromatosis type 2 (NF2): diagnosis and management. Handb Clin Neurol. 2013; 115:957-67. doi: 10.1016/B978-0-444-52902-2.00054-0. PMID: 23931824
  8. Hoa, M, Slattery, WH. Neurofibromatosis 2. Otolaryngol. Clin. North Am. 2012; 45(2):315-32, viii. doi: 10.1016/j.otc.2011.12.005. PMID: 22483819
  9. Evans, DG. Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet. Med. 2009; 11(9):599-610. doi: 10.1097/GIM.0b013e3181ac9a27. PMID: 19652604
  10. Blakeley, JO, et al. Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2. Am. J. Med. Genet. A. 2012; 158A(1):24-41. doi: 10.1002/ajmg.a.34359. PMID: 22140088
  11. Kluwe, L, et al. Screening for large mutations of the NF2 gene. Genes Chromosomes Cancer. 2005; 42(4):384-91. doi: 10.1002/gcc.20138. PMID: 15645494
  12. Evans, DG, et al. A clinical study of type 2 neurofibromatosis. Q. J. Med. 1992; 84(304):603-18. PMID: 1484939
  13. Smith, MJ, et al. Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. J. Med. Genet. 2011; 48(4):261-5. doi: 10.1136/jmg.2010.085241. PMID: 21278391

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
NF2 NM_000268.3
SMARCB1 NM_003073.3