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.


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. 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
  2. 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
  3. Evans, DG, et al. A clinical study of type 2 neurofibromatosis. Q. J. Med. 1992; 84(304):603-18. PMID: 1484939
  4. 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
  5. 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
  6. Evans, DG. Neurofibromatosis 2. 1998 Oct 14. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301380
  7. 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
  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. 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
  10. 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
  11. 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
  12. 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
  13. 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

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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