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Clinical and Molecular Characteristics of 1qter Syndrome: Delineating a Critical Region for corpus callosum agenesis/hypogenesis
  1. Bregje W.M. van Bon (b.vanbon{at}antrg.umcn.nl)
  1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    1. David A. Koolen
    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
      1. Renato Borgatti
      1. RCCS Eugenio Medea La Nostra Famiglia, Bosisio Parini, Lecco, Italy
        1. Alex Magee
        1. IRCCS Eugenio Medea La Nostra Famiglia, Bosisio Parini, Lecco, Italy
          1. Sixto Garcia-Minaur
          1. South East of Scotland Clinical Genetic Service, Western General Hospital, Edinburgh, United Kingdom
            1. Liesbeth Rooms
            1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
              1. William Reardon
              1. National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Republic of Ireland
                1. Marcella Zollino
                1. Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy
                  1. Maria C Bonaglia
                  1. Northern Ireland Regional Genetics Service, Belfast City Hospital Trust, Belfast, Republic of Ireland
                    1. Manuela De gregori
                    1. Genetica Medica, Università di Pavia, Pavia, Italy
                      1. Francesca Novara
                      1. Genetica Medica, Università di Pavia, Pavia, Italy
                        1. Rita Grasso
                        1. IRCCS Eugenio Medea La Nostra Famiglia, Bosisio Parini, Lecco, Italy
                          1. Roberto Ciccone
                          1. Genetica Medica, Università di Pavia, Pavia, Italy
                            1. Hermine A. van Duyvenvoorde
                            1. Depts of Clinical Genetics, Dept of Pediatrics and Dept of Endocrinology and Metabolism, Leiden, Netherlands
                              1. Anna M. Aalbers
                              1. Depts of Clinical Genetics, Dept of Pediatrics and Dept of Endocrinology and Metabolism, Leiden, Netherlands
                                1. Renzo Guerrini
                                1. Azienda Ospedaliero-Universitaria A. Meyer, Clinica di Neurologia Pediatrica, Firenze, Italy
                                  1. Elisa Fazzi
                                  1. Dept of Child Neurology and Psychiatry, IRCCS C. Mondino Institute of Neurology, Pavia, Italy
                                    1. Willy M. Nillesen
                                    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                      1. Simon McCullough
                                      1. Northern Ireland Regional Genetics Service, Belfast City Hospital Trust, Belfast, Republic of Ireland
                                        1. Sarina G. Kant
                                        1. Depts of Clinical Genetics, Dept of Pediatrics and Dept of Endocrinology and Metabolism, Leiden, Netherlands
                                          1. Carlo L. Marcelis
                                          1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                            1. Rolph Pfundt
                                            1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                              1. Nicole de Leeuw
                                              1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                                1. Dominique Smeets
                                                1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                                  1. Erik A. Sistermans
                                                  1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                                    1. Jan M. Wit
                                                    1. Depts of Clinical Genetics, Dept of Pediatrics and Dept of Endocrinology and Metabolism, Leiden, Netherlands
                                                      1. Ben C. Hamel
                                                      1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                                        1. Han G. Brunner
                                                        1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
                                                          1. Frank Kooy
                                                          1. Department of Medical Genetics, University of Antwerp, Antwerp, Netherlands
                                                            1. Orsetta Zuffardi
                                                            1. Genetica Medica, Università di Pavia, Pavia, Netherlands
                                                              1. Bert B.A. de Vries (b.devries{at}antrg.umcn.nl)
                                                              1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

                                                                Abstract

                                                                Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. In the present study we describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and we report on the molecular characterisation of the deletion size. The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in ten of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalites to a 0.36 Mb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.

                                                                • 1qter microdeletion
                                                                • AKT3
                                                                • ZNF238
                                                                • corpus callosum agenesis

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