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Further clinical and molecular delineation of the 9q Subtelomeric Deletion Syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype
  1. Tjitske Kleefstra (t.kleefstra{at}antrg.umcn.nl)
  1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    1. Wendy A van Zelst-Stams (w.stams{at}gen.unimaas.nl)
    1. Department of Clinical Genetics, Maastricht University Hospital, Maastricht, Netherlands
      1. Willy M Nillesen (w.nillesen{at}antrg.umcn.nl)
      1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
        1. Valerie Cormier-Daire (cormier{at}necker.fr)
        1. Department of Medical Genetics and INSERM U781, Hôpital Necker Enfants Malades, Paris, France
          1. Gunnar Houge (gunnar.houge{at}helse-bergen.no)
          1. Center for medical genetics and molecular medicine, Haukeland University Hospital, Bergen, Norway
            1. Nicola Foulds (nicola.foulds{at}suht.swest.nhs.uk)
            1. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
              1. Marieke van Dooren (m.vandooren{at}erasmusmc.nl)
              1. Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, Netherlands
                1. Marjolein H Willemsen (m.willemsen{at}antrg.umcn.nl)
                1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                  1. Rolph Pfundt (r.pfundt{at}antrg.umcn.nl)
                  1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                    1. Anne Turner (anne.turner{at}sesiahs.health.nsw.gov.au)
                    1. Department of Medical Genetics, Sydney Children's Hospital, Randwick, Sydney, Australia
                      1. Meredith Wilson (merediw{at}chw.edu.au)
                      1. Department of Clinical Genetics, Children’s Hospital at Westmead, Sydney, Australia
                        1. Julie McGaughran (julie_mcgaughran{at}health.qld.gov.au)
                        1. Genetic Health Queensland, Royal Children's Hospital and Health District, Herston, Brisbane, Australia
                          1. Anita Rauch (anita.rauch{at}humgenet.uni-erlangen.de)
                          1. Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlange, Germany
                            1. Martin Zenker (martin.zenker{at}humgenet.uni-erlangen.de)
                            1. Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlange, Germany
                              1. Margaret Adam (madam{at}genetics.emory.edu)
                              1. Emory University, Atlanta, Georgia, United States
                                1. Micheil Innes
                                1. Department of Clinical Genetics, Alberta Children's Hospital, Calgary, Canada
                                  1. Christine Davies
                                  1. Department of Clinical Genetics, Alberta Children's Hospital, Calgary, Canada
                                    1. Antonio González-Meneses López (antonio.gonzalezmeneses.l.sspa{at}juntadeandalucia.es)
                                    1. Unidad de Dismorfología, Servicio de Pediatría,Hospital UniversitarioVirgendel Rocío, Sevilla, Spain
                                      1. Rosario Casalone (rosario.casalone{at}ospedale.varese.it)
                                      1. Dipartimento di Patologia Clinica, S.S. di Genetica Medica, Azienda Ospedaliero Universitaria, Vares, Italy
                                        1. Astrid Weber (astrid.weber{at}lwh.nhs.uk)
                                        1. Alder Hey Children’s Hospital, Liverpool, United Kingdom
                                          1. Louise A Brueton (louise.brueton{at}bwhct.nhs.uk)
                                          1. Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham, United Kingdom
                                            1. Alicia Delicado Navarro
                                            1. Sección de Genética Médica, Hospital Universitario La Paz, Madrid, Spain
                                              1. Maria Palomares Bralo
                                              1. Sección de Genética Médica, Hospital Universitario La Paz, Madrid, Spain
                                                1. Hanka Venselaar
                                                1. Center for Molecular and Biomolecular Informatics, Radboud University Nijmegen, Netherlands
                                                  1. Sander P A Stegmann (sander.stegmann{at}gen.unimaas.nl)
                                                  1. Department of Human Genetics, Maastricht University Hospital, Maastricht, Netherlands
                                                    1. Helger G Yntema (h.ijntema{at}antrg.umcn.nl)
                                                    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                                      1. Hans van Bokhoven (h.vanbokhoven{at}antrg.umcn.nl)
                                                      1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                                        1. Han G Brunner (h.brunner{at}antrg.umcn.nl)
                                                        1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

                                                          Abstract

                                                          The 9q Subtelomeric Deletion Syndrome (9qSTDS) is clinically characterized by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioral problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases.

                                                          Here we report the largest cohort of 9qSTDS cases so far. By a Multiplex Ligation dependent Probe Amplification approach, we identified and characterized 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion, identified 6 patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein.

                                                          Our data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, we confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype.

                                                          Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.

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