NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

Authors

  • Eric Pasmant,

    Corresponding author
    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
    2. Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Boulevard du Général Leclerc, 92110, Clichy, France
    • UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75006, Paris, France
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  • Audrey Sabbagh,

    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
    2. Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Boulevard du Général Leclerc, 92110, Clichy, France
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  • Gill Spurlock,

    1. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, Cf14 4XN, UK
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  • Ingrid Laurendeau,

    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
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  • Elisa Grillo,

    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
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  • Marie-José Hamel,

    1. Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Boulevard du Général Leclerc, 92110, Clichy, France
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  • Ludovic Martin,

    1. Service de Dermatologie, CHU d'Angers, Université d'Angers, 49933 Angers Cedex 9, France
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  • Sébastien Barbarot,

    1. Service de Dermatologie, Hôtel Dieu, CHU de Nantes, 44093, Nantes, France
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  • Bruno Leheup,

    1. Service de Médecine Infantile III et Génétique Clinique, Hôpital d'Enfants CHU de Nancy, Faculté de Médecine Nancy Université Henri Poincaré, Vandoeuvre, France
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  • Diana Rodriguez,

    1. AP-HP, Hôpital Armand Trousseau, Service de Neuropédiatrie, Paris, France
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  • Didier Lacombe,

    1. Service de Génétique Médicale, Hôpital Pellegrin, CHU de Bordeaux, Université de Bordeaux 2, 33076, Bordeaux, France
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  • Hélène Dollfus,

    1. Laboratoire de Génétique Médicale EA 3949, Equipe Avenir-Inserm, Faculté de Médecine de Strasbourg, Université de Strasbourg, 67000, Strasbourg, France
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  • Laurent Pasquier,

    1. CNRS UMR6061 Génétique et Développement, Université de Rennes 1, IFR140, Rennes, France
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  • Bertrand Isidor,

    1. Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes 7, Quai Moncousu, 44000 Nantes Cedex, France
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  • Salah Ferkal,

    1. INSERM, Centre d'Investigation Clinique 006, AP-HP, Groupe hospitalier Henri Mondor-Albert Chenevier, Créteil, F-94000, France
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  • Jean Soulier,

    1. INSERM U944, Hôpital Saint-Louis, Paris; et Plateforme Génomique Institut Universitaire d'Hématologie (IUH), Université Paris Diderot, Hôpital Saint-Louis, Paris, France
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  • Marc Sanson,

    1. Service de Neurologie Mazarin, INSERM UMR-975, Hôpital de la Salpêtrière, 75013, Paris, France
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  • Anne Dieux-Coeslier,

    1. Service de Génétique Clinique, Hôpital Jeanne de Flandre, 59000, Lille, France
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  • Ivan Bièche,

    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
    2. Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Boulevard du Général Leclerc, 92110, Clichy, France
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  • Béatrice Parfait,

    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
    2. Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Boulevard du Général Leclerc, 92110, Clichy, France
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  • Michel Vidaud,

    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
    2. Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Boulevard du Général Leclerc, 92110, Clichy, France
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  • Pierre Wolkenstein,

    1. Département of Dermatologie, AP-HP and Université Paris 12, Hôpital Henri-Mondor, 94000, Créteil, France
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  • Meena Upadhyaya,

    1. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, Cf14 4XN, UK
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  • Dominique Vidaud

    1. UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France
    2. Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Boulevard du Général Leclerc, 92110, Clichy, France
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  • Communicated by Dominque Stoppa-Lyonnet

Abstract

In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP–c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotype-phenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent ∼1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP–c. © 2010 Wiley-Liss, Inc.

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