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Clinical and molecular delineation of the 17q21.31 microdeletion syndrome
  1. David A Koolen (d.koolen{at}antrg.umcn.nl)
  1. Radboud University Nijmegen Medical Centre, Netherlands
    1. Andy J Sharp
    1. University of Geneva Medical School CMU, Switzerland
      1. Jane A Hurst
      1. Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, United Kingdom
        1. Helen V Firth
        1. Addenbrooke's Hospital, United Kingdom
          1. Samantha JL Knight
          1. Wellcome Trust Centre for Human Genetics, Churchill Hospital, United Kingdom
            1. Alice Goldenberg
            1. Rouen University Hospital, & Inserm U614, Institute for Biomedical research, University of Rouen, France
              1. Pascale Saugier-Veber
              1. Rouen University Hospital, & Inserm U614, Institute for Biomedical research, University of Rouen, France
                1. Rolph Pfundt
                1. Radboud University Nijmegen Medical Centre, Netherlands
                  1. Lisenka ELM Vissers
                  1. Radboud University Nijmegen Medical Centre, Netherlands
                    1. Anne Destrée
                    1. Institut de Pathologie et de Génétique, Belgium
                      1. Bernard Grisart
                      1. Institut de Pathologie et de Génétique, Belgium
                        1. Liesbeth Rooms
                        1. University of Antwerp, Antwerp, Belgium
                          1. Nathalie Van der Aa
                          1. Antwerp University Hospital, Belgium
                            1. Michael Field
                            1. Hunter New England Area Health Service, Australia
                              1. Anna Hackett
                              1. Hunter New England Area Health Service, Australia
                                1. Kathleen Bell
                                1. McMaster University Medical Centre, Canada
                                  1. Malgorzatta JM Nowaczyk
                                  1. McMaster University, Canada
                                    1. Grazia MS Mancini
                                    1. Erasmus Medical Center, Netherlands
                                      1. Pino J Poddighe
                                      1. Erasmus Medical Center, Netherlands
                                        1. Charles E Schwartz
                                        1. Greenwood Genetic Center, United States
                                          1. Elena Rossi
                                          1. Università di Pavia, Italy
                                            1. Manuela De Gregori
                                            1. Università di Pavia, Italy
                                              1. Lucinda L Antonacci-Fulton
                                              1. Washington University School of Medicine, United States
                                                1. Michael D McLellan II
                                                1. Washington University School of Medicine, United States
                                                  1. Joseph M Garrett
                                                  1. Washington University School of Medicine, United States
                                                    1. Madeline A Wiechert
                                                    1. Washington University School of Medicine, United States
                                                      1. Tracie L Miner
                                                      1. Washington University School of Medicine, United States
                                                        1. Seth Crosby
                                                        1. Washington University School of Medicine, United States
                                                          1. Roberto Ciccone
                                                          1. Università di Pavia, Italy
                                                            1. lionel willatt (lionel.willatt{at}addenbrookes.nhs.uk)
                                                            1. Addenbrooke's Hospital, United Kingdom
                                                              1. Anita Rauch
                                                              1. University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Germany
                                                                1. Martin Zenker
                                                                1. University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Germany
                                                                  1. Swaroop Aradhya
                                                                  1. Stanford University School of Medicine, United States
                                                                    1. Melanie A Manning
                                                                    1. Stanford University School of Medicine, United States
                                                                      1. Tim M Strom
                                                                      1. GSF National Research Center for Environment and Health, Germany
                                                                        1. Janine Wagenstaller
                                                                        1. GSF National Research Center for Environment and Health, Germany
                                                                          1. Ana C Krepischi-Santos
                                                                          1. Institute of Biosciences, University of São Paulo, Brazil
                                                                            1. Angela M Vianna-Morgante
                                                                            1. Institute of Biosciences, University of São Paulo, Brazil
                                                                              1. Carla Rosenberg
                                                                              1. Institute of Biosciences, University of São Paulo, Brazil
                                                                                1. Susan M Price
                                                                                1. Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, United Kingdom
                                                                                  1. Helen Stewart
                                                                                  1. Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, United Kingdom
                                                                                    1. Charles Shaw-Smith
                                                                                    1. Addenbrooke's Hospital, United Kingdom
                                                                                      1. Han G Brunner
                                                                                      1. Radboud University Nijmegen Medical Centre, Netherlands
                                                                                        1. Andrew OM Wilkie
                                                                                        1. University of Oxford, John Radcliffe Hospital, United Kingdom
                                                                                          1. Joris A Veltman
                                                                                          1. Radboud University Nijmegen Medical Centre, Netherlands
                                                                                            1. Orsetta Zuffardi
                                                                                            1. Università di Pavia, Italy
                                                                                              1. Evan E Eichler
                                                                                              1. University of Washington School of Medicine, United States
                                                                                                1. Bert BA de Vries (b.devries{at}antrg.umcn.nl)
                                                                                                1. Radboud University Nijmegen Medical Centre, Netherlands

                                                                                                  Abstract

                                                                                                  The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high-resolution genome analyses in patients with unexplained mental retardation. Here we report the molecular and/or clinical characterization of 22 individuals with the 17q21.31 microdeletion syndrome. We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination, reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behavior are the most characteristic features. Other clinically important features include epilepsy, heart defects (ASD, VSD), and kidney/ urologic anomalies. Using high-resolution oligonucleotide arrays, we narrow the 17q21.31 critical region to a 424-kb genomic segment (chr17: 41046729-41470954, hg17), encompassing at least six genes, among which the gene encoding microtubule-associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease-associated variants. In five deletion carriers, we identify a <500-bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined, the parent originating the deletion carries a common 900-kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10-5). Our data establishes the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognizable genomic disorder.

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