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  • Test code: 04168
  • 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 Schwannomatosis Panel

Test description

The Invitae Schwannomatosis Panel analyzes the LZTR1, NF2 and SMARCB1 genes, associated with hereditary schwannomatosis.

Testing may be considered in any individual with multiple schwannomas or a family history of schwannomatosis. Individuals with a pathogenic variant are at increased risk of developing multiple schwannomas, primarily along peripheral nerves, that often cause chronic, severe pain that can be debilitating. This test can also distinguish schwannomatosis from neurofibromatosis type 2 (NF2), prior to the development of vestibular schwannomas. Vestibular schwannomas are a hallmark of NF2 and usually develop by 30 years of age; however, vestibular schwannomas are absent in isolated, nonsyndromic schwannomatosis. Individuals with multiple schwannomas may eventually fulfill NF2 diagnostic criteria and some isolated cases are mosaic for a pathogenic variant in NF2. 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 of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

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Primary panel (3 genes)
  • schwannomatosis
  • rhabdoid Tumor Predisposition SyndromeCoffin-Siris syndrome
  • Noonan syndrome

Schwannomatosis is a rare form of neurofibromatosis that results in multiple schwannomas (a benign myelin sheath tumor derived from Schwann cells). Schwannomas arise primarily along the peripheral nerves but they can also appear along intracranial nerves and/or the spinal nerve root. Schwannomatosis is distinguished from neurofibromatosis type 2 (NF2) in that there are no concomitant bilateral vestibular schwannomas—a diagnostic criterion of NF2.

Those affected with schwannomatosis generally present in the second or third decade of life with chronic, severe pain and neurologic dysfunction if the schwannoma impedes on a nerve or surrounding tissue. Overall, symptomatology is widely variable and is dependent upon where schwannomas are located. Additional symptoms can include tingling, weakness due to nerve or spinal cord compression, difficulty with urination or bowel dysfunction, facial weakness, headaches, vision changes, and lumps or swollen areas where tumors form under the skin. Malignant transformation rarely occurs. Some individuals may also develop meningiomas (generally benign tumors of meningeal tissue). Up to one third of affected individuals present with a segmental or mosaic form of schwannomatosis, in which schwannomas are localized to one limb or five or fewer spinal segments. Life expectancy is normal, but there can be significant morbidity depending upon the location of the schwannomas.

It is difficult to more definitively describe the sensitivity of this test in individuals with schwannomatosis, as a majority of sporadic schwannomatosis cases, as well as individuals with multiple meningiomas, have no known causative mutation.

Single schwannomas occur frequently in the general population and these cases are generally sporadic. The inheritance of schwannomatosis is not well understood and only 15%-25% of such cases are considered hereditary. Hereditary forms due to pathogenic variants in LZTR1, NF2 and SMARCB1 exhibit autosomal dominant inheritance with highly variable expressivity and incomplete penetrance. While most cases of schwannomatosis are inherited from a parent, 10%-30% are the result of a spontaneous de novo mutation (10% for schwannomatosis due to SMARCB1 and 30% for LZTR1). Approximately 25%-30% of simplex NF2 cases are mosaic for an NF2 pathogenic variant.

Schwannomatosis exhibits highly variable expressivity and incomplete penetrance. While penetrance is reduced, the specific lifetime risk of developing schwannomas is currently not established.

The exact incidence of inherited nonsyndromic schwannomatosis is not definitively known, but may be as common as neurofibromatosis type 2, which affects approximately 1 in 40,000 births. There is no known predilection for race or gender.

Testing for schwannomatosis may be indicated in an individual with a family history of multiple schwannomas in a first-degree relative or for diagnostic confirmation. Diagnostic criteria for schwannomatosis are available (PMID: 23401320).

Clinical diagnosis:

  • Two or more non-intradermal schwannomas, one with pathological confirmation, including no bilateral vestibular schwannoma by high-quality MRI (detailed study of internal auditory canal with slices no more than 3 mm thick)
    • Some with mosaic NF2 will be included in this diagnosis at a young age and some with schwannomatosis have been reported to have unilateral vestibular schwannomas or multiple meningiomas.
  • One pathologically confirmed schwannoma or intracranial meningioma and an affected first-degree relative

Consider schwannomatosis as a possible diagnosis if there are:

  • Two or more non-intradermal tumors but none has been pathologically proven to be a schwannoma
  • The occurrence of chronic pain in association with schwannoma(s) increases the likelihood of schwannomatosis.

  1. MacCollin, M, et al. Diagnostic criteria for schwannomatosis. Neurology. 2005; 64(11):1838-45. doi: 10.1212/01.WNL.0000163982.78900.AD. PMID: 15955931
  2. 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
  3. Koontz, NA, et al. Schwannomatosis: the overlooked neurofibromatosis?. AJR Am J Roentgenol. 2013; 200(6):W646-53. doi: 10.2214/AJR.12.8577. PMID: 23701098
  4. Hulsebos, TJ, et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am. J. Hum. Genet. 2007; 80(4):805-10. doi: 10.1086/513207. PMID: 17357086
  5. Westhout, FD, et al. Recognizing schwannomatosis and distinguishing it from neurofibromatosis type 1 or 2. J Spinal Disord Tech. 2007; 20(4):329-32. doi: 10.1097/BSD.0b013e318033ee0f. PMID: 17538359
  6. Plotkin, SR, et al. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am. J. Med. Genet. A. 2013; 161A(3):405-16. doi: 10.1002/ajmg.a.35760. PMID: 23401320
  7. Sestini, R, et al. Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum. Mutat. 2008; 29(2):227-31. doi: 10.1002/humu.20679. PMID: 18072270
  8. 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
  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. Curto, M, McClatchey, AI. Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. Br. J. Cancer. 2008; 98(2):256-62. doi: 10.1038/sj.bjc.6604002. PMID: 17971776
  11. 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
  12. 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
  13. 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
  14. Piotrowski, A, et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat. Genet. 2014; 46(2):182-7. PMID: 24362817
  15. Lu-Emerson, C, Plotkin, SR. The neurofibromatoses. Part 2: NF2 and schwannomatosis. Rev Neurol Dis. 2009; 6(3):E81-6. PMID: 19898272
  16. 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
  17. 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
  18. Friedman, JM. Neurofibromatosis 1. 1998 Oct 02. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1109/ PMID: 20301288
  19. Smith, MJ, et al. Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology. 2015; 84(2):141-7. PMID: 25480913
  20. Paganini, I, et al. Expanding the mutational spectrum of LZTR1 in schwannomatosis. Eur. J. Hum. Genet. 2015; 23(7):963-8. PMID: 25335493
  21. Smith, MJ, et al. SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors. Cancer Genet. 2014; 207(9):373-8. PMID: 24933152
  22. Bourdeaut, F, et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin. Cancer Res. 2011; 17(1):31-8. PMID: 21208904

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
LZTR1 NM_006767.3
NF2 NM_000268.3
SMARCB1 NM_003073.3