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Comment on Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1

European Journal of Human Genetics volume 31, pages 380–382 (2023)Cite this article

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Neurofibromatosis type 1 (NF1; MIM#162200) represents one of the most frequent autosomal dominant conditions with a worldwide birth incidence of 1 in 2500. Though fully penetrant, the disease shows an important variable expressivity among patients and over time. NF1 frequent manifestations include pigmentary manifestations (café-au-lait spots, skinfold freckling, and Lisch nodules), skeletal abnormalities (scoliosis and long bone dysplasia), behavioral symptoms (cognitive impairment, attention-deficit/hyperactivity disorder, and autism spectrum disorder), and tumors (peripheral nerve sheath tumors, and gliomas). Other, albeit rare, manifestations include juvenile xanthogranuloma, pheochromocytomas and gastrointestinal stromal tumors.

NF1 is caused by germline heterozygous loss-of-function variants in the NF1 gene (MIM#613113), located at 17q11.2. NF1 comprises 58 constitutive and two alternative exons and spans over ~280 kb. The 8517-nucleotide open reading frame of the NF1 gene (NM_001042492.3) encodes a 2839-amino-acid protein, neurofibromin, which shows tumor suppressor function by negatively regulating the RAS-MAPK pathway. There is a very large number of different loss-of-function NF1 pathogenic variants which were identified; for example, more than 3700 unique NF1 variants (mostly germline variants) have been reported in the Global Variome shared Leiden Open Variation Database. NF1 pathogenic variants are distributed through the entire coding region and splice sites with no hotspot. A significant part of these variations corresponds to large rearrangements [1, 2].

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Fig. 1: Complementary molecular analysis showing double multi-exon deletions.

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Authors and Affiliations

  1. Fédération de Génétique et Médecine Génomique, Hôpital Cochin, DMU BioPhyGen, AP-HP.Centre-Université Paris Cité, Paris, France

    Laurence Pacot, Albain Chansavang, Ingrid Laurendeau, Djihad Hadjadj, Dominique Vidaud & Eric Pasmant

  2. Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France

    Laurence Pacot, Albain Chansavang, Sébastien Jacques, Dominique Vidaud & Eric Pasmant

  3. Department of Dermatology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Créteil, France

    Salah Ferkal & Pierre Wolkenstein

  4. INSERM, Centre d’Investigation Clinique 1430, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Referral Center of Neurofibromatosis, Créteil, France

    Salah Ferkal & Pierre Wolkenstein

Authors
  1. Laurence Pacot
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  2. Albain Chansavang
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  8. Dominique Vidaud
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  9. Eric Pasmant
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Contributions

All authors made substantial contributions to the work, as follows: SF and PW participated in patient recruitment and primary clinical data collection; DV supervised and performed the initial genetic analysis and variant validation; LP, AC, SJ, IL, and DH made substantial contributions to additional molecular genetic experiments; LP and AC performed the genetic analyses; EP and LP substantially contributed to study concept and design and manuscript writing, analysis and interpretation of data.

Corresponding author

Correspondence to Eric Pasmant.

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The authors declare no competing interests.

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The study is in line with the current French legislation on genetic studies.

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Pacot, L., Chansavang, A., Jacques, S. et al. Comment on Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1. Eur J Hum Genet 31, 380–382 (2023). https://doi.org/10.1038/s41431-023-01304-0

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  • DOI: https://doi.org/10.1038/s41431-023-01304-0

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