Phenotypic and genotypic overlap between mosaic NF2 and schwannomatosis in patients with multiple non-intradermal schwannomas

Abstract

Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated schwannomatosis versus mosaic NF2 in these patients very difficult.

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References

  1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Asai K, Tani S, Mineharu Y, Tsurusaki Y, Imai Y, Agawa Y, Iwaki K, Matsumoto N, Sakai (2015) Familial schwannomatosis with a germline mutation of SMARCB1 in Japan. Brain Tumor Pathol 32:216–220

    Article  PubMed  CAS  Google Scholar 

  3. Baser ME, Contributors to the International NF2 Mutation Database (2006) The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene. Hum Mutat 27:297–306

    Article  PubMed  CAS  Google Scholar 

  4. Bourn D, Carter SA, Mason S, Gareth D, Evans R, Strachan T (1994) Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. Hum Mol Genet 3:813–816

    Article  PubMed  CAS  Google Scholar 

  5. Boyd C, Smith MJ, Kluwe L, Balogh A, MacCollin M, Plotkin SR (2008) Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clin Genet 74:358–366

    Article  PubMed  CAS  Google Scholar 

  6. Castellanos E, Bielsa I, Carrato C, Rosas I, Solanes A, Hostalot C, Amilibia E, Prades J, Roca-Ribas F, Lázaro C, Blanco I, Serra E, NF2 Multidisciplinary Clinics HUGTiP-ICO-IMPPC (2015) Segmental neurofibromatosis type 2: discriminating two hit from four hit in a patient presenting multiple schwannomas confined to one limb. BMC Med Genom 8:2

    Article  Google Scholar 

  7. Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Evans DG, Mason S, Huson SM, Ponder M, Harding AE, Strachan T (1997) Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: a clinical and molecular study. J Neurol Neurosurg Psychiatry 62:361–366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Evans DG, Wallace AJ, Wu CL, Trueman L, Ramsden RT, Strachan T (1998a) Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis. Am J Hum Genet 63:727–736

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Evans DG, Trueman L, Wallace A, Collins S, Strachan T (1998b) Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet 35:450–455

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Evans DG, Ramsden RT, Shenton A, Gokhale C, Bowers NL, Huson SM, Pichert G, Wallace A (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 44:424–428

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Gripp KW, Baker L, Kandula V, Piatt J, Walter A, Chen Z, Messiaen L (2017) Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager. Clin Genet 92:540–543

    Article  PubMed  CAS  Google Scholar 

  13. Hadfield KD, Newman WG, Bowers NL, Wallace A, Bolger C, Colley A, McCann E, Trump D, Prescott T, Evans DG (2008) Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet 45:332–339

    Article  PubMed  CAS  Google Scholar 

  14. Hadfield KD, Smith MJ, Urquhart JE, Wallace AJ, Bowers NL, King AT, Rutherford SA, Trump D, Newman WG, Evans DG (2010) Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas. Oncogene 29:6216–6221

    Article  PubMed  CAS  Google Scholar 

  15. Halliday D, Emmanouil B, Pretorius P, MacKeith S, Painter S, Tomkins H, Evans DG, Parry A (2017) Genetic severity score predicts clinical phenotype in NF2. J Med Genet 54:657–664

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P (2007) Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 80:805–810

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Hutter S, Piro RM, Reuss DE, Hovestadt V, Sahm F, Farschtschi S, Kehrer-Sawatzki H, Wolf S, Lichter P, von Deimling A, Schuhmann MU, Pfister SM, Jones DT, Mautner VF (2014) Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants. Acta Neuropathol 128:449–452

    Article  PubMed  CAS  Google Scholar 

  18. Irving RM, Moffat DA, Hardy DG, Barton DE, Xuereb JH, Maher ER (1994) Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma. Hum Mol Genet 3:347–350

    Article  PubMed  CAS  Google Scholar 

  19. Jacoby LB, Jones D, Davis K, Kronn D, Short MP, Gusella J, MacCollin M (1997) Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Am J Hum Genet 61:1293–1302

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schäffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C; Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG (2018) Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. https://doi.org/10.1038/gim.2017.249 (Epub ahead of print)

    Article  PubMed  PubMed Central  Google Scholar 

  21. Jordan JT, Smith MJ, Walker JA, Erdin S, Talkowski ME, Merker VL, Ramesh V, Cai W, Harris GJ, Bredella MA, Seijo M, Suuberg A, Gusella JF, Plotkin SR (2018) Pain correlates with germline mutation in schwannomatosis. Medicine (Baltimore) 97:e9717

    Article  CAS  Google Scholar 

  22. Kehrer-Sawatzki H, Farschtschi S, Mautner VF, Cooper DN (2017) The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis. Hum Genet 136:129–148

    Article  PubMed  CAS  Google Scholar 

  23. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310-315

    Article  PubMed Central  CAS  Google Scholar 

  24. Kluwe L, Mautner VF (1998) Mosaicism in sporadic neurofibromatosis 2 patients. Hum Mol Genet 7:2051–2055

    Article  PubMed  CAS  Google Scholar 

  25. Kluwe L, Bayer S, Baser ME, Hazim W, Haase W, Fünsterer C, Mautner VF (1996) Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes. Hum Genet 98:534–548

    Article  PubMed  CAS  Google Scholar 

  26. Kluwe L, Mautner V, Heinrich B, Dezube R, Jacoby LB, Friedrich RE, MacCollin M (2003) Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet 40:109–114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Lee JD, Kwon TJ, Kim UK, Lee WS (2012) Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas. PLoS One 7:e30418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG (2016) Analysis of protein-coding genetic variation in 60,706 humans. Exome Aggreg Consort Nat 536:285–291

    CAS  Google Scholar 

  29. MacCollin M, Ramesh V, Jacoby LB, Louis DN, Rubio MP, Pulaski K, Trofatter JA, Short MP, Bove C, Eldridge R et al (1994) Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet 55:314–320

    PubMed  PubMed Central  CAS  Google Scholar 

  30. MacCollin M, Willett C, Heinrich B, Jacoby LB, Acierno JS Jr, Perry A, Louis DN (2003) Familial schwannomatosis: exclusion of the NF2 locus as the germline event. Neurology 60:1968–1974

    Article  PubMed  CAS  Google Scholar 

  31. Mehta GU, Feldman MJ, Wang H, Ding D, Chittiboina P (2016) Unilateral vestibular schwannoma in a patient with schwannomatosis in the absence of LZTR1 mutation. J Neurosurg 5:1–3

    Google Scholar 

  32. Merker VL, Esparza S, Smith MJ, Stemmer-Rachamimov A, Plotkin SR (2012) Clinical features of schwannomatosis: a retrospective analysis of 87 patients. Oncologist 17:1317–1322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Mohyuddin A, Neary WJ, Wallace A, Wu CL, Purcell S, Reid H, Ramsden RT, Read A, Black G, Evans DG (2002) Molecular genetic analysis of the NF2 gene in young patients with unilateral vestibular schwannomas. J Med Genet 39:315–322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Moyhuddin A, Baser ME, Watson C, Purcell S, Ramsden RT, Heiberg A, Wallace AJ, Evans DG (2003) Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet 40:459–463

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Murray AJ, Hughes TA, Neal JW, Howard E, Evans DG, Harper PS (2006) A case of multiple cutaneous schwannomas; schwannomatosis or neurofibromatosis type 2? J Neurol Neurosurg Psychiatry 77:269–271

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Paganini I, Mancini I, Baroncelli M, Arena G, Gensini F, Papi L, Sestini R (2014) Application of COLD-PCR for improved detection of NF2 mosaic mutations. J Mol Diagn 16:393–399

    Article  PubMed  CAS  Google Scholar 

  38. Paganini I, Chang VY, Capone GL, Vitte J, Benelli M, Barbetti L, Sestini R, Trevisson E, Hulsebos TJ, Giovannini M, Nelson SF, Papi L (2015) Expanding the mutational spectrum of LZTR1 in schwannomatosis. Eur J Hum Genet 23:963–968

    Article  PubMed  CAS  Google Scholar 

  39. Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF (1996) Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet 59:529–539

    PubMed  PubMed Central  CAS  Google Scholar 

  40. Piotrowski A, Xie J, Liu YF, Poplawski AB, Gomes AR, Madanecki P, Fu C, Crowley MR, Crossman DK, Armstrong L, Babovic-Vuksanovic D, Bergner A, Blakeley JO, Blumenthal AL, Daniels MS, Feit H, Gardner K, Hurst S, Kobelka C, Lee C, Nagy R, Rauen KA, Slopis JM, Suwannarat P, Westman JA, Zanko A, Korf BR, Messiaen LM (2014) Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet 46:182–187

    Article  PubMed  CAS  Google Scholar 

  41. Plotkin SR, Blakeley JO, Evans DG, Hanemann CO, Hulsebos TJ, Hunter-Schaedle K, Kalpana GV, Korf B, Messiaen L, Papi L, Ratner N, Sherman LS, Smith MJ, Stemmer-Rachamimov AO, Vitte J, Giovannini M (2013) Update from the 2011 international schwannomatosis workshop: from genetics to diagnostic criteria. Am J Med Genet Part A 161A:405–416

    Article  PubMed  Google Scholar 

  42. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B et al (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515–521

    Article  PubMed  CAS  Google Scholar 

  43. Rousseau G, Noguchi T, Bourdon V, Sobol H, Olschwang S (2011) SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis. BMC Neurol 11:9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361–362

    Article  PubMed  CAS  Google Scholar 

  45. Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L (2008) Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis associated schwannomas. Hum Mutat 29:227–231

    Article  PubMed  CAS  Google Scholar 

  46. Smith MJ, Higgs JE, Bowers NL, Halliday D, Paterson J, Gillespie J, Huson SM, Freeman SR, Lloyd S, Rutherford SA, King AT, Wallace AJ, Ramsden RT, Evans DG (2011) 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 48:261–265

    Article  PubMed  CAS  Google Scholar 

  47. Smith MJ, Wallace AJ, Bowers NL, Rustad CF, Woods CG, Leschziner GD, Ferner RE, Evans DG (2012) Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 13:141–145

    Article  PubMed  CAS  Google Scholar 

  48. Smith MJ, Isidor B, Beetz C, Williams SG, Bhaskar SS, Richer W, O’Sullivan J, Anderson B, Daly SB, Urquhart JE, Fryer A, Rustad CF, Mills SJ, Samii A, du Plessis D, Halliday D, Barbarot S, Bourdeaut F, Newman WG, Evans DG (2015) Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology 84:141–147

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Smith MJ, Bowers NL, Bulman M, Gokhale C, Wallace AJ, King AT, Lloyd SK, Rutherford SA, Hammerbeck-Ward CL, Freeman SR, Evans DG (2017) Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology 88:87–92

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Spyra M, Otto B, Schön G, Kehrer-Sawatzki H, Mautner VF (2015) Determination of the mutant allele frequency in patients with neurofibromatosis type 2 and somatic mosaicism by means of deep sequencing. Genes Chromosom Cancer 54:482–488

    Article  PubMed  CAS  Google Scholar 

  51. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K et al (1993) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 75:826

    Article  PubMed  CAS  Google Scholar 

  52. Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A, Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, Majewski J, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR (2015) Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet 52:413–421

    Article  PubMed  CAS  Google Scholar 

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Kehrer-Sawatzki, H., Kluwe, L., Friedrich, R.E. et al. Phenotypic and genotypic overlap between mosaic NF2 and schwannomatosis in patients with multiple non-intradermal schwannomas. Hum Genet 137, 543–552 (2018). https://doi.org/10.1007/s00439-018-1909-9

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