{
  "abstract": "Purpose Williams-Beuren syndrome (WBS) is a well-known neurodevelopmental disorder caused by a copy-number loss at the 7q11.23 locus. Although the 1.5–1.8 Mb recurrent deletion carries several genes of interest, no single gene has been identified in which pathogenic variants cause a neurodevelopmental phenotype. At this locus, GTF2I, encoding the general transcription factor II-I, has been considered as the main candidate gene for the cognitive and behavioural phenotype of WBS, based on clinical observations of cases with atypical 7q.11.23 deletions and functional studies in humans and mice.Methods Individuals with a neurodevelopmental disorder were identified through a multicentre collaboration using GeneMatcher and the ERN-ITHACA network. They remained undiagnosed following genome/exome sequencing. Clinical evaluations were performed in each participating centre.Results We identified seven unrelated individuals with de novo variants in GTF2I (two non-sense, two splice-site, one missense, one indel and one intragenic deletion). We also identified one individual with a WBS phenotype and low GTF2I expression identified by RNA sequencing. All eight individuals presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in seven cases. The effect of the two splice-site variants was confirmed by RNA sequencing.Conclusion Pathogenic heterozygous GTF2I variants cause a neurodevelopmental disorder characterised by global developmental delay with facial dysmorphic features, partly resembling the phenotype observed in individuals affected with WBS.",
  "authors": [
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France"
      ],
      "name": "Jeanne Jury"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France",
        "Institut du thorax, Nantes, Pays de la Loire, France"
      ],
      "name": "Thomas Besnard"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France",
        "Institut du thorax, Nantes, France"
      ],
      "name": "Wallid Deb"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Régional Universitaire de Tours, Tours, Centre-Val de Loire, France"
      ],
      "name": "Annick Toutain"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Régional Universitaire de Tours, Tours, Centre-Val de Loire, France"
      ],
      "name": "Paul Gueguen"
    },
    {
      "affiliations": [
        "Laboratoire de Génomique médicale—Centre NEOMICS, University Hospital Centre Dijon Bourgogne, Dijon, Bourgogne-Franche-Comté, France",
        "INSERM—Université Bourgogne, UMR1231, Dijon, Bourgogne-Franche-Comté, France"
      ],
      "name": "Ange-Line Bruel"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands"
      ],
      "name": "Arjan Bouman"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands",
        "ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands"
      ],
      "name": "Danielle Veenma"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands",
        "ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands"
      ],
      "name": "Tahsin Stefan Barakat"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France"
      ],
      "name": "Laura Do Souto Ferreira"
    },
    {
      "affiliations": [
        "Department of Human Genetics, Amsterdam University Medical Centres, Amsterdam, Noord-Holland, Netherlands"
      ],
      "name": "Petra J G Zwijnenburg"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany"
      ],
      "name": "Sarah Schuhmann"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany",
        "Centre for Rare Diseases Erlangen (ZSEER), Universitätsklinikum Erlangen, Erlangen, Bayern, Germany"
      ],
      "name": "Georgia Vasileiou"
    },
    {
      "affiliations": [
        "LNEC U1084, CHU de Poitiers, Laboratoire de Génétique Biologique, Service de Génétique Médicale, F-86000, University of Poitiers, Poitiers, Nouvelle-Aquitaine, France",
        "GCS AURAGEN, Lyon, France"
      ],
      "name": "Matthieu Egloff"
    },
    {
      "affiliations": [
        "LNEC U1084, CHU de Poitiers, Laboratoire de Génétique Biologique, Service de Génétique Médicale, F-86000, University of Poitiers, Poitiers, Nouvelle-Aquitaine, France",
        "GCS AURAGEN, Lyon, France"
      ],
      "name": "Frédéric Bilan"
    },
    {
      "affiliations": [
        "Unité de Génétique Clinique, Service de Génétique Médicale, F-86000, CHU Poitiers, Poitiers, Nouvelle-Aquitaine, France"
      ],
      "name": "Anne Mercier"
    },
    {
      "affiliations": [
        "Unité de Génétique Clinique, Service de Génétique Médicale, F-86000, CHU Poitiers, Poitiers, Nouvelle-Aquitaine, France"
      ],
      "name": "Pascaline Letard"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Duisburg, NRW, Germany"
      ],
      "name": "Elsa Leitão"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Duisburg, NRW, Germany"
      ],
      "name": "Christopher Schroeder"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Duisburg, NRW, Germany"
      ],
      "name": "Christel Depienne"
    },
    {
      "affiliations": [
        "Multi-site Medical Biology Laboratory SeqOIA, Paris, France"
      ],
      "name": "Pierre Blanc"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France",
        "Institut du thorax, Nantes, Pays de la Loire, France"
      ],
      "name": "Stéphane Bézieau"
    },
    {
      "affiliations": [
        "Multi-site Medical Biology Laboratory SeqOIA, Paris, France",
        "Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France"
      ],
      "name": "Benjamin Cogné"
    },
    {
      "affiliations": [
        "Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France",
        "Institut du thorax, Nantes, Pays de la Loire, France"
      ],
      "name": "Bertrand Isidor"
    }
  ],
  "title": "Heterozygous alterations of GTF2I at the Williams-Beuren syndrome’s locus cause a neurodevelopmental disorder",
  "uid": "6d102ccf-7f4c-5c10-8984-6ca0a562aab2"
}