No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients
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Neurofibromatosis type 1 (NF1) is a common monogenic disorder whereby affected individuals are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs, occurring in ~15 to 20 % of cases). So far, no definite genotype–phenotype correlation determining NF1 patients at risk for tumor formation has been described, although enrichment for mutations in the 5′ region of the NF1 gene in OPG patients has been suggested. We used whole exome sequencing, targeted sequencing, and copy number analysis to screen 77 unrelated NF1 patients with (n = 41) or without (n = 36; age ≥10 years) optic pathway glioma for germline NF1 alterations. We identified germline NF1 mutations in 69 of 77 patients (90 %), but no genotype–phenotype correlation was observed. Our data using a larger patient cohort did not confirm the previously reported clustering of mutations in the 5′ region of the NF1 gene in patients with OPG. Thus, NF1 mutation location should not currently be used as a clinical criterion to assess the risk of developing OPGs.
KeywordsPhenotype Correlation Exome Sequencing Optic Pathway Glioma Exome Enrichment Somatic Copy Number Alteration
We thank Laura Sieber, Linda Linke, Andrea Wittmann and the German Cancer Research Center Genomics and Proteomics Core Facility for technical support and sequencing services, and Barbara Hutter for analytical support. This work was supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (DKH, #109252) and the German Federal Ministry of Education and Research (BMBF, #01KU1201A), and by the Bundesverband Neurofibromatose e.V., Germany. S.M.W. received funding through an SNSF early postdoc mobility fellowship (P2ELP3_155365) and an EMBO long-term fellowship (ALTF 755-2014).
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Conflict of interest
The authors declare no competing financial interests.
- Bolcekova A, Nemethova M, Zatkova A, Hlinkova K, Pozgayova S, Hlavata A, Kadasi L, Durovcikova D, Gerinec A, Husakova K, Pavlovicova Z, Holobrada M, Kovacs L, Ilencikova D (2013) Clustering of mutations in the 5′ tertile of the NF1 gene in Slovakia patients with optic pathway glioma. Neoplasma 60:655–665. doi: 10.4149/neo_2013_084 CrossRefPubMedGoogle Scholar
- Garrison E, Marth G (2012) Haplotype-based variant detection from short-read sequencing. arXiv:1207.3907v2Google Scholar
- 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. doi: 10.1007/s00401-014-1311-1 CrossRefPubMedGoogle Scholar
- Mautner VF, Kluwe L, Friedrich RE, Roehl AC, Bammert S, Hogel J, Spori H, Cooper DN, Kehrer-Sawatzki H (2010) Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet 47:623–630. doi: 10.1136/jmg.2009.075937 CrossRefPubMedGoogle Scholar
- Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD (2000) Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 15:541–555. doi: 10.1002/1098-1004(200006)15:6<541:AID-HUMU6>3.0.CO;2-N CrossRefPubMedGoogle Scholar
- Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bieche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D, Members of the NFFN (2010) NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat 31:E1506–18. doi: 10.1002/humu.21271
- Pasmant E, Parfait B, Luscan A, Goussard P, Briand-Suleau A, Laurendeau I, Fouveaut C, Leroy C, Montadert A, Wolkenstein P, Vidaud M, Vidaud D (2014) Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet. doi: 10.1038/ejhg.2014.145 PubMedGoogle Scholar
- Sharif S, Upadhyaya M, Ferner R, Majounie E, Shenton A, Baser M, Thakker N, Evans DG (2011) A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations. J Med Genet 48:256–260. doi: 10.1136/jmg.2010.081760 CrossRefPubMedGoogle Scholar
- Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, Evans DG, Howard E, Kerr B, Griffiths S, Consoli C, Side L, Adams D, Pierpont M, Hachen R, Barnicoat A, Li H, Wallace P, Van Biervliet JP, Stevenson D, Viskochil D, Baralle D, Haan E, Riccardi V, Turnpenny P, Lazaro C, Messiaen L (2007) An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet 80:140–151. doi: 10.1086/510781 CrossRefPubMedPubMedCentralGoogle Scholar