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Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands
  1. Laurence Faivre (laurence.faivre{at}chu-dijon.fr)
  1. Centre de Génétique, CHU Dijon, France
    1. Gwenaelle Collod-Beroud
    1. INSERM, U827, Montpellier, F-34000, France
      1. Bart L Loeys
      1. Center for Medical Genetics, Ghent University Hospital, Belgium
        1. Anne Child
        1. Department of Cardiological Sciences, St. George's Hospital, London, United Kingdom
          1. Christine Binquet
          1. Inserm, CIE1, Dijon, France
            1. Elodie Gautier
            1. Inserm, CIE1, Dijon, France
              1. Bert Callewaert
              1. Center for Medical Genetics, Ghent University Hospital, Belgium
                1. Eloisa Arbustini
                1. Centre for Inherited Cardiovascular Diseases, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
                  1. Karen Mayer
                  1. Center for Human Genetics and Laboratory Medicine, Martinsried, Germany
                    1. Mine Arslan-Kirchner
                    1. Institute of Human Genetics, Hannover Medical School, Hannover, Germany
                      1. Chantal Stheneur
                      1. AP-HP, Hôpital Ambroise Paré, Service de Pédiatrie, Boulogne, F-92100, France
                        1. Anatolia Kiotsekoglu
                        1. Department of Cardiological Sciences, St. George's Hospital, London, United Kingdom
                          1. Paolo Comeglio
                          1. Department of Cardiological Sciences, St. George's Hospital, London, United Kingdom
                            1. Nicolai Narziliano
                            1. Centre for Inherited Cardiovascular Diseases, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
                              1. Dorothy Halliday
                              1. Department of Biochemistry, University of Oxford, United Kingdom
                                1. Christophe Beroud
                                1. CHU Montpellier, Laboratoire de Génétique Moléculaire, Hôpital Arnault de, France
                                  1. Claire Bonithon-Kopp
                                  1. Inserm, CIE1, Dijon, France
                                    1. Mireille Claustres
                                    1. CHU Montpellier, Laboratoire de Génétique Moléculaire, Hôpital Arnault de, France
                                      1. Henri Plauchu
                                      1. Service de Génétique, Hôtel Dieu, Lyon, France
                                        1. Peter N Robinson
                                        1. Institut für Medizinische Genetik, Universitätsmedizin Charité, Berlin, Germany
                                          1. Lesly Ades
                                          1. Marfan Research Group, The Children’s Hospital at Westmead, Sydney, Australia
                                            1. Julie De Backer
                                            1. Center for Medical Genetics, Ghent University Hospital, Belgium
                                              1. Paul Coucke
                                              1. Center for Medical Genetics, Ghent University Hospital, Belgium
                                                1. Uta Francke
                                                1. Departments of Genetics and Pediatrics, Stanford University Medical Center, United States
                                                  1. Anne De Paepe
                                                  1. Center for Medical Genetics, Ghent University Hospital, Belgium
                                                    1. Catherine Boileau
                                                    1. Laboratoire de Génétique moléculaire, Hôpital Ambroise Paré, AP-HP, France
                                                      1. Guillaume Jondeau
                                                      1. Consultation pluridisciplinaire Marfan, Hôpital Bichat, AP-HP, Paris, France

                                                        Abstract

                                                        Background: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening.

                                                        Methods: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as fulfilling or not "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not the "clinical" international criteria.

                                                        Results: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85% respectively. Aortic dilatation occurred later in adults with unfillfilled "clinical criteria" when compared to the Marfan syndrome group (44% versus 73% at 40 years, p<0•001) but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups.

                                                        Conclusions: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of outmost importance in patients without aortic dilatation and in children.

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