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Neurological Sciences

Erschienen in:

05.06.2021 | Original Article

Deletion of the whole NF1 gene in a three-generation family with neurofibromatosis type 1

verfasst von: Qin Du, Hongxi Chen, Hongyu Zhou

Erschienen in: Neurological Sciences | Ausgabe 2/2022

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Abstract

Background

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder characterized by café-au-lait macules (CALMs), skinfold freckling, Lisch nodules, and neurofibromas. It is associated with heterozygous mutations in the neurofibromatosis type 1 (NF1) gene. Whole NF1 deletion has been described in some cases, but most cases are sporadic, and familial forms are extremely rare. To date, only two-generation familial forms have been described.

Objective

To describe a whole NF1 gene deletion in a three-generation family with neurofibromatosis type 1.

Methods

Physical examinations, laboratory tests, structural neuroimaging studies, whole-exome sequencing, and multiplex ligation-dependent probe amplification analysis were carried out.

Results

All the affected individuals within this three-generation family, including the 14-year-old female proband, her 40-year-old father, and 63-year-old grandmother, exhibited such typical manifestations of NF1 as CALMs and cutaneous neurofibromas, CALMs increased in size with age. The affected subjects had more localized hyperpigmentation and CALMs within the lesion areas, mainly in the chest, abdomen, waist, and back. In addition, learning disorder was observed in the proband, and brain MRI revealed abnormal high signal lesions in the brainstem. All the affected subjects had normal birth history and had no significant past medical history. Whole-exome sequencing and subsequent multiplex ligation-dependent probe amplification analysis identified deletion of the whole NF1 gene, co-segregating with the NF1 phenotype in an autosomal dominant pattern.

Conclusions

Our findings are the first to identify whole NF1 deletion in a three-generation family with autosomal dominant NF1 and broaden the understanding of the genetic spectrum of NF1-associated NF1.

Carey JC, Baty BJ, Johnson JP, Morrison T, Skolnick M, Kivlin J (1986) The genetic aspects of neurofibromatosis. Ann NY Acad Sci 486(none):45–56CrossRef

Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL (2009) Neurofibromatosis type 1 revisited. Pediatrics 123(1):124–133. https://doi.org/10.1542/peds.2007-3204CrossRefPubMed

Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A (2006) Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44(2):81–88. https://doi.org/10.1136/jmg.2006.045906CrossRefPubMedPubMedCentral

Palma Milla C, Lezana Rosales JM, López Montiel J, Andrés Garrido LD, Sánchez Linares C, Carmona Tamajón S, Torres Fernández C, Sánchez González P, Franco Freire S, Benito López C, López Siles J (2018) Neurofibromatosis type I: mutation spectrum of NF1 in Spanish patients. Ann Hum Genet 82(6):425–436. https://doi.org/10.1111/ahg.12272CrossRefPubMed

Bonatti F, Adorni A, Matichecchia A, Mozzoni P, Uliana V, Pisani F, Garavelli L, Graziano C, Gnoli M, Carli D, Bigoni S, Boschi E, Martorana D, Percesepe A (2017) Patterns of novel alleles and genotype/phenotype correlations resulting from the analysis of 108 previously undetected mutations in patients affected by neurofibromatosis type I. Int J Mol Sci 18(10). https://doi.org/10.3390/ijms18102071

RiccardiLewis VMRAJAJoHG (1988) Penetrance of von Recklinghausen neurofibromatosis: a distinction between predecessors and descendants. Am J Hum Genet 42(2):284–289

Chong JA, Moran MM, Teichmann M, Kaczmarek JS, Roeder R, Clapham DE (2005) TATA-Binding Protein (TBP)-Like Factor (TLF) Is a functional regulator of transcription: reciprocal regulation of the neurofibromatosis type 1 and c-fos genes by TLF/TRF2 and TBP. Mol Cell Biol 25(7):2632–2643. https://doi.org/10.1128/mcb.25.7.2632-2643.2005CrossRefPubMedPubMedCentral

Michel, Bahuau, Anna, Pelet, Dominique, Vidaud, Thierry, Lamireau, Brigitte, Genetics LJJoM (2001) GDNF as a candidate modifier in a type 1 neurofibromatosis (NF1) enteric phenotype. J Med Genet 38(9):638–643

Pasmant E, Vidaud M, Vidaud D, Wolkenstein P (2012) Neurofibromatosis type 1: from genotype to phenotype. J Med Genet 49(8):483–489. https://doi.org/10.1136/jmedgenet-2012-100978CrossRefPubMed

10.

Titze S, Peters H, Währisch S, Harder T, Guse K, Buske A, Tinschert S, Harder A (2009) Differential MSH2 promoter methylation in blood cells of Neurofibromatosis type 1 (NF1) patients. Eur J Hum Genet 18(1):81–87. https://doi.org/10.1038/ejhg.2009.129CrossRefPubMedCentral

11.

Valero MC, Pascual-Castroviejo I, Velasco E, Moreno F, Genetics CH-CJH (1997) Identification of de novo deletions at the NF1 gene: no preferential paternal origin and phenotypic analysis of patients. Hum Genet 99(6):720–726CrossRef

12.

Ko JM, Sohn YB, Jeong SY, Kim H-J, Messiaen LM (2013) Mutation spectrum of NF1 and Clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol 48(6):447–453. https://doi.org/10.1016/j.pediatrneurol.2013.02.004CrossRefPubMed

13.

Serra E, Lázaro C, Garcia-Linares C, Terribas E (2013) Probe-based quantitative PCR assay for detecting constitutional and somatic deletions in the NF1 gene: application to genetic testing and tumor analysis. Clin Chem 59(6):928–937. https://doi.org/10.1373/clinchem.2012.194217CrossRefPubMed

14.

Banerjee S, Dai Y, Liang S, Chen H, Wang Y, Tang L, Wu J, Huang H (2016) A novel mutation in NF1 is associated with diverse intra-familial phenotypic variation and astrocytoma in a Chinese family. J Clin Neurosci 31:182–184. https://doi.org/10.1016/j.jocn.2015.12.034CrossRefPubMed

15.

Boyd KP, Korf BR, Theos A (2009) Neurofibromatosis type 1. J Am Acad Dermatol 61(1):1–14. https://doi.org/10.1016/j.jaad.2008.12.051CrossRefPubMedPubMedCentral

16.

Jadayel D, Fain P, Upadhyaya M, Ponder MA, Huson SM, Carey J, Fryer A, Mathew CGP, Barker DF, Ponder BAJJN (1990) Paternal origin of new mutations in Von Recklinghausen neurofibromatosis. Nature 343(6258):558–559CrossRef

17.

Karen Stephens LK, Riccardi VM, Rising M, Sybert VP, Pagon RA (1992) Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum Genet 88(3):279–282

18.

Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BAJJHG (1998) Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum Genet 102(5):591–597CrossRef

19.

Edwards JH, Huson S, Ponder BJL (1988) Neurofibromatosis Lancet 2(8606):330CrossRef

20.

Su SY, Zhou X, Pang XM, Chen CY, Li SH, Liu JL (2016) NF1 frameshift mutation (c.6520_6523delGAGA) association with nervous system tumors and bone abnormalities in a Chinese patient with neurofibromatosis type 1. Genet Mol Res 15(2). https://doi.org/10.4238/gmr.15027572

21.

Calì F, Chiavetta V, Ruggeri G, Piccione M, Romano VJEjomg (2016) Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform. Eur J Med Genet 60(2):93–99

22.

Kang E, Kim Y-M, Seo GH, Oh A, Yoon HM, Ra Y-S, Kim EK, Kim H, Heo S-H, Kim G-H, Osborn MJ, Tolar J, Yoo H-W, Lee BH (2019) Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet 65(2):79–89. https://doi.org/10.1038/s10038-019-0695-0CrossRefPubMed

23.

Kayes LM, Burke W, Riccardi VM, Bennett R, Stephens KJAJoHG, (1994) Deletions spanning the neurofibromatosis 1 gene: identification and phenotype of five patients. Am J Hum Genet 54(3):424PubMedPubMedCentral

24.

Leppig KA, Viskochil D, Neil S, Rubenstein A, Johnson VP, Zhu XL, Brothman AR, Stephens KJC, genetics c, (1996) The detection of contiguous gene deletions at the neurofibromatosis 1 locus with fluorescence in situ hybridization. Cytogenet Cell Genet 72(1):95–98CrossRef

25.

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 23(5):596–601. https://doi.org/10.1038/ejhg.2014.145CrossRefPubMedPubMedCentral

26.

Sabbagh A, Pasmant E, Imbard A, Luscan A, Soares M, Blanché H, Laurendeau I, Ferkal S, Vidaud M, Pinson SJHM (2013) NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat 34(11):1510–1518CrossRef

27.

Tonsgard JH, Yelavarthi KK, Cushner S, Short MP, Lindgren VJAJoMG (1997) Do NF1 gene deletions result in a characteristic phenotype? Am J Med Genet 73(1):80–86

28.

Tsipi M, Poulou M, Fylaktou I, Kosma K, Tsoutsou E, Pons M-R, Kokkinou E, Kitsiou-Tzeli S, Fryssira H, Tzetis M (2018) Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA. J Neurol Sci 395:95–105. https://doi.org/10.1016/j.jns.2018.10.006CrossRefPubMed

29.

Ulusal SD, Gürkan H, Atlı E, Özal SA, Çiftdemir M, Tozkır H, Karal Y, Güçlü H, Eker D, Görker I (2017) Genetic analyses of the NF1 gene in Turkish neurofibromatosis type I patients and definition of three novel variants. Balkan J Med Genet 20(1):13–20. https://doi.org/10.1515/bjmg-2017-0008CrossRefPubMedPubMedCentral

30.

Wu BL, Austin MA, Schneider GH, Boles RG, Korf BRJAJoMG (1995) Deletion of the entireNF1 gene detected by FISH: four deletion patients associated with severe manifestations. Am J Med Genet 59(4):528–535

31.

Shofty B, Constantini S, Ben-Shachar S (2015) Advances in molecular diagnosis of neurofibromatosis type 1. Seminars in Pediatric Neurology 22(4):234–239. https://doi.org/10.1016/j.spen.2015.10.007CrossRefPubMed

Titel: Deletion of the whole NF1 gene in a three-generation family with neurofibromatosis type 1
verfasst von: Qin Du
Hongxi Chen
Hongyu Zhou
Publikationsdatum: 05.06.2021
Verlag: Springer International Publishing
Erschienen in: Neurological Sciences / Ausgabe 2/2022
Print ISSN: 1590-1874
Elektronische ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-021-05353-5

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Abstract

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