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Cryptic deletions are a common finding in “balanced” reciprocal and complex chromosome rearrangements: a study of 59 cases
  1. Manuela De Gregori
  1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
    1. Roberto Ciccone
    1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
      1. Pamela Magini
      1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
        1. Tiziano Pramparo
        1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
          1. Stefania Gimelli
          1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
            1. Jole Messa
            1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
              1. Francesca Novara
              1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
                1. Annalisa Vetro
                1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
                  1. Elena Rossi
                  1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
                    1. Paola Maraschio
                    1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, IRCCS Policlinico San Matteo, Pavia, Italy
                      1. Maria Clara Bonaglia
                      1. IRCCS E Medea Bosisio Parini, Lecco, Italy
                        1. Cecilia Anichini
                        1. Pediatria, Università di Siena, Siena, Italy
                          1. Giovanni Battista Ferrero
                          1. Dipartimento di Scienze Pediatriche, Università di Torino, Torino, Italy
                            1. Margherita Silengo
                            1. Dipartimento di Scienze Pediatriche, Università di Torino, Torino, Italy
                              1. Elisa Fazzi
                              1. IRCCS C. Mondino, Università di Pavia, Pavia, Italy
                                1. Adriana Zatterale
                                1. Servizio di Citogenetica ASL-NA1, Napoli, Italy
                                  1. Rita Fischetto
                                  1. Azienda Ospedaliera di Venere-Giovanni XXIII, Bari, Italy
                                    1. Carlo Previderè
                                    1. Dipartimento di Medicina Legale e Sanità Pubblica, Università di Pavia, Pavia, Italy
                                      1. Serena Belli
                                      1. Consultorio Genetico, Trento, Italy
                                        1. Alessandra Turci
                                        1. Citogenetica, Ospedale di Ravenna, Ravenna, Italy
                                          1. Giuseppe Calabrese
                                          1. Genetica Medica, università di Chieti, Chieti, Italy
                                            1. Franca Bernardi
                                            1. Patologia Genetica e Prenatale, Policlinico G. B. Rossi, Verona, Italy
                                              1. Emanuela Meneghelli
                                              1. Patologia Genetica e Prenatale, Policlinico G. B. Rossi, Verona, Italy
                                                1. Mariluce Riegel
                                                1. Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
                                                  1. Mariano Rocchi
                                                  1. Dipartimento di Genetica e Microbiologia, Università di Bari, Bari, Italy
                                                    1. Silvana Guerneri
                                                    1. Fondazione Ospedale Maggiore, Mangiagalli e Regina Elena, Milano, Italy
                                                      1. Faustina Lalatta
                                                      1. Fondazione Ospedale Maggiore, Mangiagalli e Regina Elena, Milano, Italy
                                                        1. Leopoldo Zelante
                                                        1. Servizio Genetica Medica, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
                                                          1. Corrado Romano
                                                          1. Oasi Institute for Research on Mental Retardation and Brain Aging, Troina, Italy
                                                            1. Marco Fichera
                                                            1. Oasi Institute for Research on Mental Retardation and Brain Aging, Troina, Italy
                                                              1. Teresa Mattina
                                                              1. Genetica Medica, Università di Catania, Catania, Italy
                                                                1. Giulia Arrigo
                                                                1. Ospedale San Raffaele, Milano, Italy
                                                                  1. Marcella Zollino
                                                                  1. Istituto di Genetica Medica, Policlinico A. Gimelli, Roma, Italy
                                                                    1. Sabrina Giglio
                                                                    1. Ospedale Pediatrico Meyer, Firenze, Italy
                                                                      1. Fortunato Lonardo
                                                                      1. Azienda Ospedaliera G. Rummo, Benevento, Italy
                                                                        1. Aldo Bonfante
                                                                        1. Genetica Medica, Ospedale San Bassiano, Vicenza, Italy
                                                                          1. Alessandra Ferlini
                                                                          1. Genetica Medica, Università di Ferrara, Ferrara, Italy
                                                                            1. Francisco Cifuentes
                                                                            1. Agilent Technologies, Santa Clara, California, United States
                                                                              1. Hilde Van Esch
                                                                              1. Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
                                                                                1. Liesbeth Backx
                                                                                1. Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
                                                                                  1. Albert Schinzel
                                                                                  1. Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
                                                                                    1. Joris Robert Vermeesch
                                                                                    1. Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
                                                                                      1. Orsetta Zuffardi (zuffardi{at}unipv.it)
                                                                                      1. Biologia Generale e Genetica Medica, Università di Pavia, Pavia IRCCS Policlinico San Matteo, Pavia, Italy

                                                                                        Abstract

                                                                                        Introduction and methods: We report the screening of 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) using array-CGH. All cases had been interpreted as “balanced” by conventional cytogenetics.

                                                                                        Results: Twenty-seven cases of reciprocal translocations were detected in patients with an abnormal phenotype and after array-CGH analysis eleven resulted unbalanced. Thus we found that 40% of patients with a “chromosomal phenotype” and an apparently balanced translocation were unbalanced (11 cases out of 27), and that 18% of the reciprocal translocations were instead complex rearrangements (5 cases out of 27) with more than three breakpoints. Fourteen fetuses with de novo apparently balanced translocations, all but two with normal ultrasound findings, were also analyzed and all resulted normal after array-CGH. Thirteen CCRs were detected in individuals with abnormal phenotypes, two in females with repeated abortions and three in fetuses. We found that sixteen were unbalanced with up to four deletions.

                                                                                        Discussion: Our investigations suggest that genome-wide array-CGH may be recommendable in all carriers of “balanced” CCRs. The parental origin of the deletions was investigated in five reciprocal translocations and eleven CCRs. All resulted to be paternal. Using customized platforms in seven cases of CCRs, we narrowed down the deletion breakpoints to few-hundreds base pairs and no susceptibility motifs were associated with the imbalances. Our findings demonstrate that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.

                                                                                        • array-CGH
                                                                                        • complex chromosome rearrangements
                                                                                        • cryptic deletions
                                                                                        • reciprocal translocations
                                                                                        • spermatogenesis

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