Neurofibromatosis type 1 (NF1), an autosomal dominant disorder characterized by skin pigmentary lesions and multiple cutaneous neurofibromas, is caused by neurofibromin 1 (NF1) loss of function variants. Currently, a molecular diagnosis is frequently established using a multistep protocol based on cDNA and gDNA sequence analysis and/or Multiplex Ligation-dependent Probe Amplification (MLPA) assay on genomic DNA, providing an overall detection rate of about 95–97%. The small proportion of clinically diagnosed patients, which at present do not obtain a molecular confirmation likely are mosaic, as their pathogenic variant may remain undetected due to low sensitivity of low coverage NGS approaches, or they may carry a type of pathogenic variant refractory to currently used technologies. Here, we report two unrelated patients presenting with two different inversions that disrupt the NF1 coding sequence, resulting in an NF1 phenotype. In one subject, the inversion was associated with microdeletions spanning a few NF1 exons at both breakpoints, while in the other the rearrangement did not cause exon loss, thus testing negative by MLPA assay. Considering the high proportion of repeated regions within the NF1 sequence, we propose that intragenic structural rearrangements should be considered as possible pathogenic mechanisms in patients fulfilling the NIH diagnostic criteria of NF1 but lacking of molecular confirmation and in patients with NF1 intragenic microdeletions.
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Data generated during this study have been submitted in ClinVar (ID SUB11349933, SUB11349931).
Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med. 2018;20:1082–6.
Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23:1506–13.
Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, et al. 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. 2007;80:140–51.
Smith MJ, Urquhart JE, Harkness EF, Miles EK, Bowers NL, Byers HJ, et al. The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes. Hum Mutat. 2016;37:250–6.
Rojnueangnit K, Xie J, Gomes A, Sharp A, Callens T, Chen Y, et al. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. Hum Mutat. 2015;36:1052–63.
Ruggieri M, Polizzi A, Spalice A, Salpietro V, Caltabiano R, D’Orazi V, et al. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet. 2015;87:401–10.
Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat. 2020;41:299–315.
Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, et al. Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848. Am J Hum Genet. 2018;102:69–87.
Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Prim. 2017;3:17004.
Calì F, Chiavetta V, Ruggeri G, Piccione M, Selicorni A, Palazzo D, et al. Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform. Eur J Med Genet. 2017;60:93–9.
Smith RB, Solem EP, Metz EC, Wheeler FC, Phillips JA 3rd, Yenamandra A. Clinical diagnosis of neurofibromatosis type I in multiple family members due to cosegregation of a unique balanced translocation with disruption of the NF1 locus: Testing considerations for accurate diagnosis. Am J Med Genet A. 2021;185:1222–7.
Kehrer-Sawatzki H, Mautner VF, Cooper DN. Emerging genotype-phenotype relationships in patients with large NF1 deletions. Hum Genet. 2017;136:349–76.
Ledbetter DH, Rich DC, O’connell P, Leppert M, Carey JC. Precise localization of NF1 to 17q11. 2 by balanced translocation. Am J Hum Genet. 1989;44:20–4.
Menon AG, Ledbetter DH, Rich DC, Seizinger BR, Rouleau GA, Michels VF, et al. Characterization of a translocation within the von Recklinghausen neurofibromatosis region of chromosome 17. Genomics. 1989;5:245–9.
Asamoah A, North K, Doran S, Wagstaff J, Ogle R, Collins FS, et al. 17q inversion involving the neurofibromatosis type one locus in a family with neurofibromatosis type one. Am J Med Genet. 1995;60:312–6.
Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15:541–55.
Schmidt MA, Michels VV, Dewald GW, Opitz JM, Reynolds JF. Cases of neurofibromatosis with rearrangements of chromosome 17 involving band 17q11.2. Am J Med Genet. 1987;28:771–7.
Kehrer-Sawatzki H, Häussler J, Krone W, Bode H, Jenne DE, Mehnert KU, et al. The second case of a t(17;22) in a family with neurofibromatosis type 1: sequence analysis of the breakpoint regions. Hum Genet. 1997;99:237–47.
Kurahashi H, Shaikh T, Takata M, Toda T, Emanuel BS. The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats. Am J Hum Genet. 2003;72:733–8.
Evans DG, Bowers N, Burkitt-Wright E, Miles E, Garg S, Scott-Kitching V, et al. Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. EBioMedicine. 2016;7:212–20.
Valero MC, Martín Y, Hernández-Imaz E, Marina Hernández A, Meleán G, Valero AM, et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011;13:113–22.
Mantere T, Neveling K, Pebrel-Richard C, Benoist M, van der Zande G, Kater-Baats E, et al. Optical genome mapping enables constitutional chromosomal aberration detection. Am J Hum Genet. 2021;108:1409–22.
Sabatella M, Mantere T, Waanders E, Neveling K, Mensenkamp AR, van Dijk F, et al. Optical genome mapping identifies a germline retrotransposon insertion in SMARCB1 in two siblings with atypical teratoid rhabdoid tumors. J Pathol. 2021;255:202–11.
Hastie AR, Lam ET, Pang AWC, Zhang LX, Andrews W, Lee J, et al. Rapid automated large structural variation detection in a diploid genome by nanochannel based next-generation mapping. BioRxiv. 2017. https://doi.org/10.1101/102764.
Pasmant E, Parfait B, Luscan A, Goussard P, Briand-Suleau A, Laurendeau I, et al. 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. 2015;23:596–601.
Messiaen LM, Wimmer K. NF1 mutational spectrum. In: Kaufmann D, editor. Neurofibromatoses, Vol. 16. Basel: Karger; 2008, pp, 63–77.
Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, et al. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer. 2006;45:265–76.
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The authors declare no competing interests.
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Alesi, V., Lepri, F.R., Dentici, M.L. et al. Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01153-3