System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Ppublish

PubMed: 42498698 DOI: 10.1111/cge.70215

Delineation of a Novel Mirror Syndrome: NFIC Variants Cause Syndromic Intellectual Disability With Macrocephaly.

Clin Genet 110(4):449-459

Authors: Nathalie Vanden Eynde, Lucas Hérissant, Emilie Landais, Matthieu Egloff, Marlène Rio, Geneviève Baujat, Fabienne Giuliano, Houda Karmous-Benailly, Charles Coutton, Véronique Satre, Gaëlle Vieville, Paul Kuentz, Mathilde Nizon, Claire Beneteau, Bertrand Isidor, Patrick Callier, Valentine Marquet, Eric Bieth, Jonathan Lévy, Anne-Claude Tabet, François Cartault, Sophie Scheidecker, Aurélie Gouronc, Audrey Schalk, Chloé Angélini, Perrine Pennamen, Caroline Rooryck, Slavica Trajkova, Biljana Gagachovska, Brynn Shrom-Model, Stephen R Braddock, Paul Hillman, Lingying Liu, Christina Dühring Fenger, Trine Bjørg Hammer, Ina Schanze, Martin Zenker, Martine Doco-Fenzy, Céline Poirsier, Guillaume Jouret

Affiliations

  • Laboratoire National de Santé (LNS), National Center of Genetics (NCG), Dudelange, Luxembourg.
  • Department of Genetics, Reims Univeristy Hospital, Reims, France.
  • CHU de Poitiers, Service de Génétique, Poitiers, France.
  • Department of Genetics, Necker-Enfants Malades, AP-HP, Institut Imagine, Paris, France.
  • Department of Genetics, Nice University Hospital, Nice, France.
  • Service de Génétique et Procréation, Hôpital Couple-Enfant, CHU Grenoble Alpes, Université Grenoble-Alpes, La Tronche, France.
  • Université Marie et Louis Pasteur, CHU Besançon Franche-Comté, Oncobiologie Génétique Bioinformatique, FHU TRANSLAD, Besançon, France.
  • Department of Genetics, Nantes University Hospital, Nantes, France.
  • Department of Genetics, Dijon University Hospital, Dijon, France.
  • Service de Génétique Médicale, Cytogénétique et Biologie de la Reproduction, CHU de Limoges, Limoges, France.
  • Department of Genetics, Toulouse University Hospital, Toulouse, France.
  • Department of Genetics, Robert-Debré University Hospital, Paris, France.
  • Department of Genetics, La Réunion University Hospital, Saint Denis, France.
  • Strasbourg University Hospital, Strasbourg, France.
  • CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France.
  • Department of Neurosciences Rita Levi-Montalcini, University of Torino, Turin, Italy.
  • University Clinic of Psychiatry, Faculty of Medicine, Ss. Cyril and Methodius University, Skopje, North Macedonia.
  • Saint Louis University School of Medicine, Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, St Louis, Missouri, USA.
  • Department of Pediatrics, Division of Medical Genetics, McGovern Medical School at UTHealth Houston, Houston, Texas, USA.
  • Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre, Dianalund, Denmark.
  • Amplexa Genetics, Odense, Denmark.
  • Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
  • Institut Fur Humangenetik Universitatsklinikum Magdeburg, Magdeburg, Germany.
  • Department of Genetics, Hotel Dieu University Hospital, Nantes, France.

Abstract

Nuclear factor I (NFI) transcription factors regulate neural stem and progenitor differentiation during brain development. While NFIA, NFIB, and NFIX are linked to neurodevelopmental disorders, the role of NFIC (MIM: 600729) in human disease remains unclear. This study aimed to determine whether NFIC contributes to a neurodevelopmental syndrome, define its phenotype, and assess dosage-dependent effects. We established the first cohort of 11 individuals, including NFIC deletions and single nucleotide variants. Genotype-phenotype correlations, including critical region mapping, were performed. Murine data and bioinformatics were integrated to explore underlying pathomechanisms. We report 11 individuals with NFIC variants, including four with de novo SNVs and seven with deletions encompassing the gene, of whom nine have not been previously reported. A core phenotype of syndromic intellectual disability and macrocephaly was delineated. Opposing cranial phenotypes relative to proximal 19p13.3 duplication cases support a dosage-sensitive effect and a mirror-syndrome model. NFIC-related disorder represents a novel neurodevelopmental syndrome characterized by intellectual disability and macrocephaly, highlighting the importance of NFIC dosage supporting a mirror-syndrome model.

MeSH

Megalencephaly, Phenotype, Nfi Transcription Factors, Intellectual Disability, Neurodevelopment