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MEF2C haploinsufficiency caused either by microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations
  1. Nathalie Le Meur (nathalie.lemeur{at}efs.sante.fr)
  1. Génétique, CHU de Rouen and EFS Normandie, France
    1. Muriel Holder-Espinasse
    1. Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU de Lille, France
      1. Sylvie Jaillard
      1. Laboratoire de Cytogénétique, CHU Pontchaillou, CNRS UMR 6061, Université de Rennes 1, IFR 140Rennes, France
        1. Alice Goldenberg
        1. Génétique, CHU de Rouen, France
          1. Sylvie Joriot
          1. Service de Neuropédiatrie, Hôpital Roger Salengro, CHRU de Lille, France
            1. Patrizia Amati-Bonneau
            1. Service de Génétique Médicale, CHU d'Angers et Inserm U694, Université d’Angers, France
              1. Agnès Guichet
              1. Service de Génétique Médicale, CHU d'Angers, France
                1. Magalie Barth
                1. Service de Génétique Médicale, CHU d'Angers, France
                  1. Aude Charollais
                  1. Service de Médecine Néonatale, CHU de Rouen, France
                    1. Hubert Journel
                    1. Service de Génétique Clinique, Centre Hospitalier Bretagne Atlantique, Vannes, France
                      1. Stéphane Auvin
                      1. Service de Neurologie Pédiatrique, CHU Robert Debré - APHP, Paris, France
                        1. Cécile Boucher
                        1. Génétique, CHU de Rouen, France
                          1. Jean-Pierre Kerckaert
                          1. Plateforme de Génomique Fonctionnelle, Université de Lille II, France
                            1. Véronique David
                            1. CNRS UMR 6061, Université de Rennes 1, IFR 140 and Génétique Moléculaire, CHU Pontchaillou, Rennes, France
                              1. Sylvie Manouvrier-Hanu
                              1. Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU de Lille, France
                                1. Pascale Saugier-Veber
                                1. Génétique, CHU de Rouen et Inserm U614, IHU, Université de Rouen, France
                                  1. Thierry Frébourg
                                  1. Génétique, CHU de Rouen et Inserm U614, IHU, Université de Rouen, France
                                    1. Christèle Dubourg
                                    1. CNRS UMR 6061, Université de Rennes 1, IFR 140 and Génétique Moléculaire, CHU Pontchaillou, Rennes, France
                                      1. Joris Andrieux
                                      1. Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, France
                                        1. Dominique Bonneau
                                        1. Service de Génétique Médicale, CHU d'Angers et Inserm U694, Université d’Angers, France

                                          Abstract

                                          Over the last few years, array-CGH has remarkably improved the ability to detect cryptic unbalanced rearrangements in patients presenting with syndromic mental retardation. Using whole genome oligonucleotide array-CGH, we detected 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb in 5 unrelated patients showing phenotypic similarities, namely severe mental retardation with absent speech, hypotonia and stereotypic movements. Most of the patients presented also with facial dysmorphic features, epilepsy and/or cerebral malformations. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, known to act in brain as a neurogenesis effector which regulates excitatory synapse number. In a patient presenting a similar phenotype, we subsequently identified a MEF2C nonsense mutation. Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.

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