{
  "abstract": "Background Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype–phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients.Methods We investigated a large, well-phenotyped NF1 cohort.Results We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844–848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.Conclusion The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.",
  "authors": [
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France",
        "Fédération de Génétique et Médecine Génomique, DMU BioPhyGen, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France"
      ],
      "name": "Laurence Pacot"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands",
        "GROW-School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands"
      ],
      "name": "Marinus Blok"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France",
        "Fédération de Génétique et Médecine Génomique, DMU BioPhyGen, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France"
      ],
      "name": "Dominique Vidaud"
    },
    {
      "affiliations": [
        "Department of Dermatology, Hôpital Henri Mondor, Assistance Publique-Hôpital Paris (AP-HP), Créteil, France",
        "INSERM U955, Université Paris Est Créteil (UPEC), Créteil, France"
      ],
      "name": "Laura Fertitta"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France"
      ],
      "name": "Ingrid Laurendeau"
    },
    {
      "affiliations": [
        "Fédération de Génétique et Médecine Génomique, DMU BioPhyGen, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France"
      ],
      "name": "Audrey Coustier"
    },
    {
      "affiliations": [
        "Fédération de Génétique et Médecine Génomique, DMU BioPhyGen, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France"
      ],
      "name": "Theodora Maillard"
    },
    {
      "affiliations": [
        "Fédération de Génétique et Médecine Génomique, DMU BioPhyGen, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France"
      ],
      "name": "Cécile Barbance"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France"
      ],
      "name": "Djihad Hadjadj"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France"
      ],
      "name": "Manuela Ye"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France"
      ],
      "name": "Dominique Lallemand"
    },
    {
      "affiliations": [
        "Department of Dermatology, Hôpital Henri Mondor, Assistance Publique-Hôpital Paris (AP-HP), Créteil, France",
        "INSERM U955, Université Paris Est Créteil (UPEC), Créteil, France"
      ],
      "name": "Salah Ferkal"
    },
    {
      "affiliations": [
        "Department of Genetics, AP-HP (Assistance Publique-Hôpitaux de Paris), Henri Mondor University Hospital, Créteil, France"
      ],
      "name": "Benoit Funalot"
    },
    {
      "affiliations": [
        "Department of Genetics, AP-HP (Assistance Publique-Hôpitaux de Paris), Henri Mondor University Hospital, Créteil, France"
      ],
      "name": "Ariane Lunati-Rozie"
    },
    {
      "affiliations": [
        "Department of Genetics, AP-HP (Assistance Publique-Hôpitaux de Paris), Henri Mondor University Hospital, Créteil, France"
      ],
      "name": "Bérénice Hebrard"
    },
    {
      "affiliations": [
        "Department of Ophthalmology, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, France"
      ],
      "name": "Rakia Bhouri"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands"
      ],
      "name": "Liesbeth Spruijt"
    },
    {
      "affiliations": [
        "Department of Dermatology and Reference Center for Rare Skin Diseases MAGEC-Sud Montpellier, Filière Maladies Rares Dermatologiques (FIMARAD), Saint-Eloi Hospital, and University of Montpellier, Montpellier, France"
      ],
      "name": "Didier Bessis"
    },
    {
      "affiliations": [
        "Inserm U1183, Department of Clinical Genetics, Reference center for rare disease developmental anomaly and malformative syndrome, CHU Montpellier, and Montpellier University, Montpellier, France"
      ],
      "name": "David Geneviève"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands",
        "GROW-School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands"
      ],
      "name": "Vivian Vernimmen"
    },
    {
      "affiliations": [
        "Department of Neurology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands"
      ],
      "name": "Martinus P G Broen"
    },
    {
      "affiliations": [
        "Department of Medical Genetics, Children's Hospital La Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France"
      ],
      "name": "Sabine Sigaudy"
    },
    {
      "affiliations": [
        "Service de génétique clinique, CLAD Ouest, CHU Rennes, Hôpital Sud, Rennes, France"
      ],
      "name": "Sylvie Odent"
    },
    {
      "affiliations": [
        "Service de génétique clinique, CLAD Ouest, CHU Rennes, Hôpital Sud, Rennes, France"
      ],
      "name": "Léna Damaj"
    },
    {
      "affiliations": [
        "Service de génétique clinique, CLAD Ouest, CHU Rennes, Hôpital Sud, Rennes, France"
      ],
      "name": "Chloé Quélin"
    },
    {
      "affiliations": [
        "Service de génétique clinique, CLAD Ouest, CHU Rennes, Hôpital Sud, Rennes, France"
      ],
      "name": "Laurent Pasquier"
    },
    {
      "affiliations": [
        "Consultations de Génétique, Groupe Hospitalier du Havre, Le Havre, France"
      ],
      "name": "Valérie Layet"
    },
    {
      "affiliations": [
        "Service de Génétique, CHU de Poitiers, Poitiers, France"
      ],
      "name": "Brigitte Gilbert-Dussardier"
    },
    {
      "affiliations": [
        "Department of Genetics and reference center for developmental abnormalities, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, France"
      ],
      "name": "Gaël Nicolas"
    },
    {
      "affiliations": [
        "Department of Genetics and reference center for developmental abnormalities, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, France"
      ],
      "name": "Anne-Marie Guerrot"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Hôpitaux de Brabois, CHRU de Nancy, Vandoeuvre-lès-Nancy, France"
      ],
      "name": "Bruno Leheup"
    },
    {
      "affiliations": [
        "Department of Dermatology, CHRU Nancy, Vandoeuvre-lès-Nancy, France"
      ],
      "name": "Anne-Claire Bursztejn"
    },
    {
      "affiliations": [
        "Clinique de Génétique, Centre de Référence Anomalies du Développement, Univ. Lille, CHU Lille, Lille, France"
      ],
      "name": "Florence Petit"
    },
    {
      "affiliations": [
        "Clinique de Génétique, Centre de Référence Anomalies du Développement, Univ. Lille, CHU Lille, Lille, France"
      ],
      "name": "Odile Boute-Bénéjean"
    },
    {
      "affiliations": [
        "UF de Génétique Clinique, CHU Robert Debré, Paris, France"
      ],
      "name": "Yline Capri"
    },
    {
      "affiliations": [
        "Service de Médecine Génomique des Maladies Rares et Institut Imagine UMR-1163 Inserm, Université Paris Cité, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France"
      ],
      "name": "Anne Guimier"
    },
    {
      "affiliations": [
        "Service de Médecine Génomique des Maladies Rares et Institut Imagine UMR-1163 Inserm, Université Paris Cité, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France"
      ],
      "name": "Stanislas Lyonnet"
    },
    {
      "affiliations": [
        "Service de Médecine Génomique des Maladies Rares et Institut Imagine UMR-1163 Inserm, Université Paris Cité, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France"
      ],
      "name": "Genevieve Baujat"
    },
    {
      "affiliations": [
        "Department of Dermatology, MAGEC-Nord Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France"
      ],
      "name": "Emmanuelle Bourrat"
    },
    {
      "affiliations": [
        "Medical Genetics Department, CHU de Nantes, Hôtel Dieu Hospital, Nantes, France"
      ],
      "name": "Bertrand Isidor"
    },
    {
      "affiliations": [
        "Medical Genetics Department, CHU de Nantes, Hôtel Dieu Hospital, Nantes, France"
      ],
      "name": "Mathilde Nizon"
    },
    {
      "affiliations": [
        "Department of Dermatology, CHU Nantes, INRAE, UMR 1280, PhAN, Nantes University, Nantes, France"
      ],
      "name": "Sébastien Barbarot"
    },
    {
      "affiliations": [
        "Department of Genetics, Bretonneau University Hospital, Tours, France",
        "UMR 1253, iBrain, University of Tours, Inserm, Tours, France"
      ],
      "name": "Annick Toutain"
    },
    {
      "affiliations": [
        "Department of Genetics, Bretonneau University Hospital, Tours, France"
      ],
      "name": "Sophie Blesson"
    },
    {
      "affiliations": [
        "Département de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France"
      ],
      "name": "Julien Van-Gils"
    },
    {
      "affiliations": [
        "Pediatric Dermatology Unit, National Center for Rare Skin Disorders, University Hospital of Bordeaux, Bordeaux, France"
      ],
      "name": "Fanny Morice-Picard"
    },
    {
      "affiliations": [
        "Service de Pédiatrie et de Génétique Médicale, CHRU Morvan, Brest, France"
      ],
      "name": "Séverine Audebert-Bellanger"
    },
    {
      "affiliations": [
        "Service de Dermatologie, Centre de Référence des Maladies rares de la peau, Hôpital Larrey, Toulouse, France"
      ],
      "name": "Juliette Mazereeuw-Hautier"
    },
    {
      "affiliations": [
        "Department of Genetics, University Hospital of Toulouse, Toulouse, France"
      ],
      "name": "Alban Ziegler"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France"
      ],
      "name": "Yves Alembik"
    },
    {
      "affiliations": [
        "Centre de Génétique Humaine, Centre Hospitalier Universitaire de Besançon, Besançon, France",
        "UMR1231 GAD, Inserm, Université de Bourgogne, Dijon, France"
      ],
      "name": "Juliette Piard"
    },
    {
      "affiliations": [
        "Centre de Génétique Humaine, Centre Hospitalier Universitaire de Besançon, Besançon, France"
      ],
      "name": "Elise Brischoux-Boucher"
    },
    {
      "affiliations": [
        "Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France"
      ],
      "name": "Léa Guerrini-Rousseau"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Diabetology, CHU Côte de Nacre, Caen, France"
      ],
      "name": "Julia Morera"
    },
    {
      "affiliations": [
        "Inserm U1081, CNRS UMR7284, IRCAN, Université Côte d'Azur, CHU de Nice, Nice, France"
      ],
      "name": "Véronique Paquis-Flucklinger"
    },
    {
      "affiliations": [
        "Service de génétique médicale, GH de l'Institut Catholique de Lille, Lille, France"
      ],
      "name": "Bruno Delobel"
    },
    {
      "affiliations": [
        "service de pédiatrie, CHU Féleix Guyon, Saint-Denis, France"
      ],
      "name": "Jean-Luc Alessandri"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France",
        "Fédération de Génétique et Médecine Génomique, DMU BioPhyGen, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France"
      ],
      "name": "Béatrice Parfait"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France",
        "Fédération de Génétique et Médecine Génomique, DMU BioPhyGen, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France",
        "Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands",
        "GROW-School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands",
        "Department of Dermatology, Hôpital Henri Mondor, Assistance Publique-Hôpital Paris (AP-HP), Créteil, France",
        "INSERM U955, Université Paris Est Créteil (UPEC), Créteil, France",
        "Department of Genetics, AP-HP (Assistance Publique-Hôpitaux de Paris), Henri Mondor University Hospital, Créteil, France",
        "Department of Ophthalmology, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, France",
        "Department of Clinical Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands",
        "Department of Dermatology and Reference Center for Rare Skin Diseases MAGEC-Sud Montpellier, Filière Maladies Rares Dermatologiques (FIMARAD), Saint-Eloi Hospital, and University of Montpellier, Montpellier, France",
        "Inserm U1183, Department of Clinical Genetics, Reference center for rare disease developmental anomaly and malformative syndrome, CHU Montpellier, and Montpellier University, Montpellier, France",
        "Department of Neurology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands",
        "Department of Medical Genetics, Children's Hospital La Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France",
        "Service de génétique clinique, CLAD Ouest, CHU Rennes, Hôpital Sud, Rennes, France",
        "Consultations de Génétique, Groupe Hospitalier du Havre, Le Havre, France",
        "Service de Génétique, CHU de Poitiers, Poitiers, France",
        "Department of Genetics and reference center for developmental abnormalities, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, France",
        "Service de Génétique Médicale, Hôpitaux de Brabois, CHRU de Nancy, Vandoeuvre-lès-Nancy, France",
        "Department of Dermatology, CHRU Nancy, Vandoeuvre-lès-Nancy, France",
        "Clinique de Génétique, Centre de Référence Anomalies du Développement, Univ. Lille, CHU Lille, Lille, France",
        "UF de Génétique Clinique, CHU Robert Debré, Paris, France",
        "Service de Médecine Génomique des Maladies Rares et Institut Imagine UMR-1163 Inserm, Université Paris Cité, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France",
        "Department of Dermatology, MAGEC-Nord Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France",
        "Medical Genetics Department, CHU de Nantes, Hôtel Dieu Hospital, Nantes, France",
        "Department of Dermatology, CHU Nantes, INRAE, UMR 1280, PhAN, Nantes University, Nantes, France",
        "Department of Genetics, Bretonneau University Hospital, Tours, France",
        "UMR 1253, iBrain, University of Tours, Inserm, Tours, France",
        "Département de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France",
        "Pediatric Dermatology Unit, National Center for Rare Skin Disorders, University Hospital of Bordeaux, Bordeaux, France",
        "Service de Pédiatrie et de Génétique Médicale, CHRU Morvan, Brest, France",
        "Service de Dermatologie, Centre de Référence des Maladies rares de la peau, Hôpital Larrey, Toulouse, France",
        "Department of Genetics, University Hospital of Toulouse, Toulouse, France",
        "Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France",
        "Centre de Génétique Humaine, Centre Hospitalier Universitaire de Besançon, Besançon, France",
        "UMR1231 GAD, Inserm, Université de Bourgogne, Dijon, France",
        "Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France",
        "Department of Endocrinology and Diabetology, CHU Côte de Nacre, Caen, France",
        "Inserm U1081, CNRS UMR7284, IRCAN, Université Côte d'Azur, CHU de Nice, Nice, France",
        "Service de génétique médicale, GH de l'Institut Catholique de Lille, Lille, France",
        "service de pédiatrie, CHU Féleix Guyon, Saint-Denis, France",
        "Genetics Department, Institut Curie, Paris, France"
      ],
      "name": "on behalf of NF-France network"
    },
    {
      "affiliations": [
        "Department of Dermatology, Hôpital Henri Mondor, Assistance Publique-Hôpital Paris (AP-HP), Créteil, France",
        "INSERM U955, Université Paris Est Créteil (UPEC), Créteil, France"
      ],
      "name": "Pierre Wolkenstein"
    },
    {
      "affiliations": [
        "Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France",
        "Genetics Department, Institut Curie, Paris, France"
      ],
      "name": "Eric Pasmant"
    }
  ],
  "title": "Refined genotype–phenotype correlations in neurofibromatosis type 1 patients with NF1 point variants",
  "uid": "77016dbb-248c-5659-a3f2-ae5ee3af59be"
}