Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
Por:
Castilla-Vallmanya L, Selmer KK, Dimartino C, Rabionet-Janssen R, Blanco-Sánchez B, Yang S, Reijnders MRF, van Essen AJ, Oufadem M, Vigeland MD, Stadheim B, Houge G, Cox H, Kingston H, Clayton-Smith J, Innis JW, Iascone M, Cereda A, Gabbiadini S, Chung WK, Sanders V, Charrow J, Bryant E, Millichap J, Vitobello A, Thauvin C, Mau-Them FT, Faivre L, Lesca G, Labalme A, Rougeot C, Chatron N, Sanlaville D, Christensen KM, Kirby A, Lewandowski R, Gannaway R, Aly M, Lehman A, Clarke L, Graul-Neumann L, Zweier C, Lessel D, Lozic B, Aukrust I, Peretz R, Stratton R, Smol T, Dieux-Coëslier A, Meira J, Wohler E, Sobreira N, Beaver EM, Heeley J, Briere LC, High FA, Sweetser DA, Walker MA, Keegan CE, Jayakar P, Shinawi M, Kerstjens-Frederikse WS, Earl DL, Siu VM, Reesor E, Yao T, Hegele RA, Vaske OM, Rego S, Undiagnosed Diseases Network, Care4Rare Canada Consortium, Shapiro KA, Wong B, Gambello MJ, McDonald M, Karlowicz D, Colombo R, Serretti A, Pais L, O'Donnell-Luria A, Wray A, Sadedin S, Chong B, Tan TY, Christodoulou J, White SM, Slavotinek A, Barbouth D, Morel Swols D, Parisot M, Bole-Feysot C, Nitschké P, Pingault V, Munnich A, Cho MT, Cormier-Daire V, Balcells S, Lyonnet S, Grinberg-Vaisman DR, Amiel J, Urreizti R and Gordon CT
Publicada:
1 jul 2020
Ahead of Print:
7 may 2020
Resumen:
PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
Filiaciones:
Castilla-Vallmanya L:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona
CIBERER, IRSJD, Barcelona, Spain
Selmer KK:
Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital and the University of Oslo, Oslo, Norway
The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway
Dimartino C:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Rabionet-Janssen R:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona
CIBERER, IRSJD, Barcelona, Spain
Blanco-Sánchez B:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Yang S:
GeneDx, Gaithersburg, MD, USA
Reijnders MRF:
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
van Essen AJ:
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
Oufadem M:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Vigeland MD:
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Stadheim B:
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
Houge G:
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
Cox H:
West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK
Kingston H:
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Academic Health Sciences Centre, Manchester, UK
Division of Evolution and Genomic Sciences, University of Manchester, School of Biological Sciences, Manchester, UK
Clayton-Smith J:
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Academic Health Sciences Centre, Manchester, UK
Division of Evolution and Genomic Sciences, University of Manchester, School of Biological Sciences, Manchester, UK
Innis JW:
Departments of Human Genetics, Pediatrics and Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Iascone M:
Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy
Cereda A:
Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy
Gabbiadini S:
Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy
Chung WK:
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA
Sanders V:
Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Charrow J:
Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
Bryant E:
Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
Millichap J:
Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
Vitobello A:
UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France
INSERM UMR1231 GAD, Dijon, France
Thauvin C:
UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France
Centre de Reference maladies rares "Anomalies du Developpement et syndrome malformatifs" de l'Est, Centre de Genetique, Hopital d'Enfants, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
Mau-Them FT:
UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France
INSERM UMR1231 GAD, Dijon, France
Faivre L:
INSERM UMR1231 GAD, Dijon, France
Centre de Reference maladies rares "Anomalies du Developpement et syndrome malformatifs" de l'Est, Centre de Genetique, Hopital d'Enfants, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
Lesca G:
Department of Medical Genetics, Lyon Hospices Civils, Lyon, France
Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Lyon, France
Labalme A:
Department of Medical Genetics, Lyon Hospices Civils, Lyon, France
Rougeot C:
Hôpital Femme Mère Enfant, Service de Neuropédiatrie, Bron, France
Chatron N:
Department of Medical Genetics, Lyon Hospices Civils, Lyon, France
Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Lyon, France
Sanlaville D:
Department of Medical Genetics, Lyon Hospices Civils, Lyon, France
Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Lyon, France
Christensen KM:
Saint Louis University School of Medicine, St. Louis, MO, USA
Kirby A:
Saint Louis University School of Medicine, St. Louis, MO, USA
Lewandowski R:
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
Gannaway R:
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
Aly M:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Lehman A:
Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada
Clarke L:
Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada
Graul-Neumann L:
Institute of Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany
Zweier C:
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Lessel D:
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Lozic B:
Department of Pediatrics, University Hospital Centre Split
University of Split, School of Medicine, Split, Croatia
Aukrust I:
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
Peretz R:
Driscoll Children's Hospital, Corpus Christi, TX, USA
Stratton R:
Driscoll Children's Hospital, Corpus Christi, TX, USA
Smol T:
Institut de Génétique Médicale, CHU Lille, Lille, France
Université de Lille, EA 7364 - RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme, Lille, France
Dieux-Coëslier A:
Institut de Génétique Médicale, CHU Lille, Lille, France
Meira J:
Division of Medical Genetics, University Hospital Professor Edgard Santos/ Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
Wohler E:
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
Sobreira N:
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
Beaver EM:
Mercy Kids Genetics, Mercy Children's Hospital, St. Louis, MO, USA
Heeley J:
Mercy Kids Genetics, Mercy Children's Hospital, St. Louis, MO, USA
Briere LC:
Division of Medical Genetics & Metabolism, Massachusetts General Hospital for Children, Boston, MA, USA
High FA:
Division of Medical Genetics & Metabolism, Massachusetts General Hospital for Children, Boston, MA, USA
Sweetser DA:
Division of Medical Genetics & Metabolism, Massachusetts General Hospital for Children, Boston, MA, USA
Walker MA:
Department of Pediatric Neurology, Massachusetts General Hospital for Children, Boston, MA, USA
Keegan CE:
Departments of Human Genetics, Pediatrics and Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Jayakar P:
Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA
Shinawi M:
Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA
Kerstjens-Frederikse WS:
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
Earl DL:
Seattle Children's Hospital, Seattle, WA, USA
Siu VM:
University of Western Ontario, London, ON, Canada
Reesor E:
University of Western Ontario, London, ON, Canada
Yao T:
University of Western Ontario, London, ON, Canada
Hegele RA:
University of Western Ontario, London, ON, Canada
Vaske OM:
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA
Rego S:
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
Shapiro KA:
Cortica Healthcare, San Diego, CA, USA
Wong B:
Cortica Healthcare, San Diego, CA, USA
Gambello MJ:
Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, GA, USA
McDonald M:
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Karlowicz D:
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Colombo R:
Faculty of Medicine, Catholic University, IRCCS Policlinico Gemelli, Rome, Italy
Center for the Study of Rare Hereditary Diseases (CeSMER), Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy
Serretti A:
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
Pais L:
Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
O'Donnell-Luria A:
Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
Wray A:
Royal Children's Hospital, Melbourne, Australia
Sadedin S:
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
Chong B:
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
Tan TY:
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
Department of Paediatrics, University of Melbourne, Melbourne, Australia
Christodoulou J:
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
Department of Paediatrics, University of Melbourne, Melbourne, Australia
White SM:
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
Department of Paediatrics, University of Melbourne, Melbourne, Australia
Slavotinek A:
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
Barbouth D:
Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA
Morel Swols D:
Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA
Parisot M:
Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker INSERM UMR1163, Paris, France
INSERM US24/CNRS UMS3633, Paris Descartes-Sorbonne Paris Cité University, Paris, France
Bole-Feysot C:
Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker INSERM UMR1163, Paris, France
INSERM US24/CNRS UMS3633, Paris Descartes-Sorbonne Paris Cité University, Paris, France
Nitschké P:
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Bioinformatics Platform, INSERM UMR 1163, Institut Imagine, Paris, France
Pingault V:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
Munnich A:
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
Cho MT:
GeneDx, Gaithersburg, MD, USA
Cormier-Daire V:
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Institut Imagine, Paris, France
Balcells S:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona
CIBERER, IRSJD, Barcelona, Spain
Lyonnet S:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
Grinberg-Vaisman DR:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona
CIBERER, IRSJD, Barcelona, Spain
Amiel J:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France
Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
Urreizti R:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona
CIBERER, IRSJD, Barcelona, Spain
Gordon CT:
Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
Green Accepted, Bronze, Green Published
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