Abstract
Neurofibromatosis (NF) is a clinically heterogeneous autosomal dominant disorder. Three distinct forms have been identified: neurofibromatosis type 1 (NF1), type 2 (NF2) and schwannomatosis. In the present study, we report clinical and genetic findings in the NF1 and NF2 genes in a cohort of 27 Bulgarian patients, with 18 cases (67%) genetically verified. Both NF1 and NF2 genes were screened by Sanger sequencing on DNA samples. The Sanger negative samples were screened by Multiplex Ligation-dependent Probe Amplification (MLPA) for deletions and duplications. The results from genetic testing revealed three novel mutations and fifteen previously reported ones (13 in the NF1 gene and 2 in the NF2 gene). The novel variants in the NF1 gene are a splice site mutation c.4725-1G>A, a small deletion of five bases c.823delATCTT, p.Leu275ValfsTer14, and a single base duplication c.6547dupC, p.Arg2183ProfsTer11. The novel splice site mutation is manifested by multiple “café au lait” macules and neurofibromas. Both novel out of frame mutations were found in patients with multiple “café au lait” spots and focal epilepsy. A segmental neurofibromatosis (SNF1) is restricted to one or more body segments. Here we present a case with SNF1 caused by a somatic deletion of exons 1 to 12 of the NF1 gene which is manifested by multiple neurofibromas in the right hand. Two nonsense mutations are found in the NF2 gene. Our study adds three novel mutations to the NF1 mutation spectra and contributes to the clinical-genetic NF1-characterization. Here we report strikingly different phenotypic spectra caused by the same mutation in a single family. Our findings contribute to the genotype- phenotype correlations which are difficult to establish, due to the extremely complex NF phenotype being a combination of clinical features.
Similar content being viewed by others
References
Huson, S.M., The neurofibromatoses: classification, clinical features and genetic counselling, Monographs in Human Genetics, Schmid, M., Ed., vol. 16: Neurofibromatoses, Kaufmann, D., Ed., Karger: Basel, 2008, pp. 1–20.
Yohay, K.H., The genetic and molecular pathogenesis of NF1 and NF2, Semin. Pediatr. Neurol., 2006, vol. 13, no. 1, pp. 21–26.
Morais, P., Ferreira, O., Bettencourt, H., and Azevedo, F., Segmental neurofibromatosis: a rare variant of a common genodermatosis, Acta Dermatovenerol. Alp. Panonica Adriat., 2010, vol. 19, pp. 27–29.
Sobjanek, M., Dobosz-Kawałko, M., Michajłowski, I., Pęksa, R., et al., Segmental neurofibromatosis, Postepy Dermatol. Alergol., 2014, vol. 31, no. 6, pp. 410–412.
Bessonova, L.A., El’chinova, G.I., and Zinchenko, R.A., Population genetics of hereditary diseases in the child population of the Republic of Bashkortostan, Chuvashia, and Udmurtia, Russ. J. Genet., 2012, vol. 48, no. 5, pp. 644–654.
Neurofibromatosis: conference statement, National Institutes of Health Consensus Development Conference, Arch. Neurol. Chicago., 1988, vol. 45, pp. 575–578.
Ferner, R.E., Huson, S.M., Thomas, N., et al., Guidelines for the diagnosis and management of individuals with neurofibromatosis 1, J. Med. Genet., 2007, vol. 44, no. 2, pp. 81–88.
García-Romero, M.T., Parkin, P., and Lara-Corrales, I., Mosaic neurofibromatosis type 1: a systematic review, Pediatr. Dermatol., 2016, vol. 33, no. 1, pp. 9–17.
Ruggieri, M., The different forms of neurofibromatosis, Childs Nerv. Syst., 1999, vol. 15, nos. 6—7, pp. 295–308.
Ruggieri, M. and Huson, S.M., The clinical and diagnostic implications of mosaicism in the neurofibromatoses, Neurology, 2001, vol. 56, pp. 1433–1443.
Ruggieri, M., Pavone, P., Polizzi, A., et al., Ophthalmological manifestations in segmental neurofibromatosis type 1, Br. J. Ophthalmol., 2004, vol. 88, pp. 1429–1433.
Ruggieri, M. and Praticò, A.D., Mosaic neurocutaneous disorders and their causes, Semin. Pediatr. Neurol., 2015, vol. 22, no. 4, pp. 207–233.
Hager, C.M., Cohen, P.R., and Tschen, J.A., Segmental neurofibromatosis: case reports and review, Am. J. Acad. Dermatol., 1997, vol. 37, pp. 864–869.
Ilyas, A.M., Nourissat, G., and Jupiter, J.B., Segmental neurofibromatosis of the hand and upper extremity: a case report, J. Hand. Surg. Am., 2007, vol. 32, no. 10, pp. 1538–1542.
Kazubskaia, T.P., Kozlova, V.M., Musatov, V.K., et al., Identification of the hereditary variants of skin melanoma, Russ. J. Genet., 2004, vol. 40, no. 1, pp. 88–96.
Shen, M.H., Harper, P.S., and Upadhyaya, M., Molecular genetics of neurofibromatosis type 1 (NF1), J. Med. Genet., 1996, vol. 33, pp. 2–17.
Fahsold, R., Hoffmeyer, S., Mischung, C., et al., Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain, Am. J. Hum. Genet., 2000, vol. 66, no. 3, pp. 790–818.
Evans, D.G., Neurofibromatosis type 2 (NF2): a clinical and molecular review, Orphanet J. Rare Dis., 2009, vol. 19, pp. 4–16.
Ruggieri, M., Praticò, A.D., and Evans, D.G., Diagnosis, management, and new therapeutic options in childhood neurofibromatosis type 2 and related forms, Semin. Pediatr. Neurol., 2015, vol. 22, no. 4, pp. 240–258.
Lloyd, S.K. and Evans, D.G., Neurofibromatosis type 2 service delivery in England, Neurochirurgie, 2016. doi 10.1016/j.neuchi.2015.10.006
Slattery, W.H., Neurofibromatosis type 2, Otolaryngol. Clin. North Am., 2015, vol. 48, no. 3, pp. 443–460.
Baser, M.E., Kuramoto, L., Joe, H., et al., Genotype—phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study, Am. J. Hum. Genet., 2004, vol. 75, pp. 231–239.
Baser, M.E., Kuramoto, L., Woods, R., et al., The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2, J. Med. Genet., 2005, vol. 42, no. 7, pp. 540–546.
Dubatolova, T.D., Kopyl, S.A., Bulgakovam, N.A., et al., Effect of mutations in Drosophila melanogaster tumor suppressor Merlin on proliferation and differentiation of wing cells, Russ. J. Genet., 2010, vol. 46, no. 2, pp. 187–193.
Dubatolova, T.D., Dorogova, N.V., Omel’ianchuk, L.V., and Chang, L.S., Duration of the cell cycle phases in mutants for the tumor suppressor Merlin in Drosophila melanogaster, Russ. J. Genet., 2011, vol. 47, no. 4, pp. 460–465.
Iudina, O.S., Gusachenko, A.M., Akhmamet’eva, E.M., and Omel’ianchuk, L.V., Chromosome nondisjunction in Drosophila strains mutant for tumor suppressor Merlin, Russ. J. Genet., 2008, vol. 44, no. 3, pp. 414–416.
Den Dunnen, J.T., Dalgleish, R., Maglott, D.R., et al., HGVS recommendations for the description of sequence variants: Human Genome Variation Society (HGVS), the Human Variome Project (HVP) and the Human Genome Organisation (HUGO), Hum. Mutat., 2016, update. doi 10.1002/humu.22981
Ferner, R. and Gutman, D., Handbook of Clinical Neurology Peripheral Nerve Disorders, Said, G. and Krarup, C., Eds., in Neurofibromatosis Type 1 (NF1): Diagnosis and Management, Elsevier, 2013, 3rd ed., pp. 939–955.
Deo, M., Huang, J.L., Fuchs, H., et al., Differential effects of neurofibromin gene dosage on melanocyte development, J. Invest. Dermatol., 2013, vol. 133, no. 1, pp. 49–58.
Abramowicz, A. and Gos, M., Neurofibromin in neurofibromatosis type 1—mutations in NF1 gene as a cause of disease, Dev. Period. Med., 2014, vol. 18, no. 3, pp. 297–306.
Castle, B., Baser, M. E., Huson, S. M., et al., Evaluation of genotype—phenotype correlations in neurofibromatosis type 1, J. Med. Genet., 2003, vol. 40. e109
Sabbagh, A., Pasmant, E., Imbard, A., et al., NF1 molecular characterization and neurofibromatosis type I genotype—phenotype correlation: the French experience, Hum. Mutat., 2013, vol. 34, no. 11, pp. 1510–1518.
Kweh, F., Zheng, M., Kurenova, E., et al., Neurofibromin physically interacts with the N-terminal domain of focal adhesion kinase, Mol. Carcinog., 2009, vol. 48, no. 11, pp. 1005–1017.
Williams, V.C., Lucas, J., Babcock, M.A., et al., Neurofibromatosis type 1 revisited, Pediatrics, 2009, vol. 123, no. 1, pp. 124–133.
Trovó-Marqui, A.B. and Tajara, E.H., Neurofibromin: a general outlook, Clin. Genet., 2006, vol. 70, no. 1, pp. 1–13.
Gammel, J.A., Localized neurofibromatosis, Arch. Dermatol. Syph., 1931, vol. 24, pp. 712–715.
Crowe, F.W., Schull, W.J., and Neel, J.V., Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis, Springfield (IL): Charles C Thomas, 1956.
Miller, R.M. and Sparkes, R.S., Segmental neurofibromatosis, Arch. Dermatol., 1977, vol. 123, pp. 837–838.
Riccardi, V.M., Neurofibromatosis: clinical heterogeneity, Curr. Probl. Cancer, 1982, vol. 7, pp. 1–34.
Roth, R.R., Martines, R., and James, W.D., Segmental neurofibromatosis, Arch. Dermatol., 1987, vol. 123, pp. 917–920.
Gorlin, R., Cohen, M.M., Jr., and Levine, M., The neurofibromatoses (NfI Recklinghausen type, NfII acoustic type, other types), in Syndromes of the Head and Neck, Gorlin, R., Cohen, M.M., Jr., and Levine, M., Eds., Oxford: Oxford University Press, 1992, pp. 392–399.
Garcia-Linares, C., Fernández-Rodríguez, J., Terribas, E., et al., Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1 associated neurofibromas: importance of copy neutral LOH, Hum. Mutat., 2011, vol. 32, no. 1, pp. 78–90.
Laczmańska, I., Szczepaniak, M., Jakubiak, A., and Stembalska, A., Exonic deletions in the NF1 gene in patients with neurofibromatosis type 1 from the lower Silesian region of Poland, Adv. Clin. Exp. Med., 2014, vol. 23, no. 4, pp. 517–521.
Evans, D.G., Trueman, L., Wallace, A., et al., Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations, J. Med. Genet., 1998, vol. 35, no. 6, pp. 450–455.
Author information
Authors and Affiliations
Corresponding author
Additional information
The article is published in the original.
Rights and permissions
About this article
Cite this article
Glushkova, M., Yordanova, I., Todorov, T. et al. Three Novel NF1 Gene Mutations in a Cohort of Bulgarian Neurofibromatoses Patients. Russ J Genet 54, 110–116 (2018). https://doi.org/10.1134/S1022795418010040
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1022795418010040