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Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort
Authors:Pleuntje J. van der Sluijs  Marieke Joosten  Caroline Alby  Tania Attié-Bitach  Kelly Gilmore  Christele Dubourg  Mélanie Fradin  Tianyun Wang  Evangeline C. Kurtz-Nelson  Kaitlyn P. Ahlers  Peer Arts  Christopher P. Barnett  Myla Ashfaq  Anwar Baban  Myrthe van den Born  Sarah Borrie  Tiffany Busa  Alicia Byrne  Gijs W.E. Santen
Affiliation:1. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;2. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, The Netherlands;3. Department of Histo-Embryology and Cytogenetics, Necker-Enfants Malades Hospital, AP-HP, Paris, France;4. National Institute of Health and Medical Research (INSERM), University of Paris, Imagine Institute, Paris, France;5. Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina School of Medicine, Chapel Hill, NC;6. Department of Molecular Genetics and Genomics, Rennes University Hospital Center (CHU), Rennes, France;7. Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France;8. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA;9. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA;10. Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia;11. Paediatric and Reproductive Genetics Unit, Women''s and Children''s Hospital, North Adelaide, South Australia, Australia;12. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia;13. Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX;14. Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children''s Hospital and Research Institute, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy;15. Service de Génétique Médicale, Hôpital de la Timone, APHM, Marseille, France; Department of Medical Genetics, Timone Hospital, APHM, Marseille, France;16. Australian Genomics, Parkville, Victoria, Australia;17. Medical Genetics, University of Siena, Siena, Italy;18. Medical Genetics Lab, Bambino Gesù Children''s Hospital and Research Institute, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy;19. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada;20. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;21. Department of Clinical and Molecular Genetics, Vall d''Hebron Barcelona Hospital Campus, Barcelona, Spain;22. Department of Pediatrics, University of Washington, Seattle, WA;23. Center for Integrative Brain Research, Seattle Children''s Research Institute, Seattle, WA;24. Department of Children and Adolescents, University Hospital Rigshospitalet, Copenhagen, Denmark;25. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;26. Aix Marseille University, INSERM, Marseille Medical Genetics, U 1251, Marseille, France;27. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark;28. Pediatrics and Adolescent Medicine, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark;29. Division of Genetic & Genomic Medicine, Nationwide Children''s Hospital, Columbus, OH;30. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH;31. Inserm UMR 1231 GAD, Genetics of Developmental Anomalies, F21000 Dijon, France;32. Functional Unit of F?tal Pathology, Pathological Anatomy Department, CHR Orleans, Orleans, France;33. Unit of Fetal Pathology, Antoine Beclere Hospital, AP-HP, Clamart, France;34. Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA;35. Department of Pathology, CHU Charles Nicolle, Rouen, France;36. Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;37. Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Hospital La Paz Institute for Health Research, Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain;38. Department of Neuropaediatrics, Charité - Berlin University of Medicine, Berlin, Germany;39. Reference Center for Rare Diseases, « Intellectual Disabilities from rare causes », CHU Dijon Bourgogne, F21000 Dijon, France;40. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands;41. Department of Medical Genetics, University of British Columbia, Children''s and Women''s Hospital, Vancouver, British Columbia, Canada;42. ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia;43. Howard Hughes Medical Institute, University of Washington, Seattle, WA;44. Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;45. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY;46. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Vagelos Medical Center, New York, NY;47. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;48. Baylor Genetics Laboratories, Houston, TX;49. Department of Obstetrics and Fetal Medicine, Leiden University Medical Center, Leiden, Netherlands;1. Genomics Education Programme, Health Education England, Birmingham, United Kingdom;2. Bristol Clinical Genetics Service, Department of Clinical Genetics, St Michael’s Hospital, Bristol, United Kingdom;3. Genomics England, London, United Kingdom;4. Wellcome Connecting Science, Wellcome Genome Campus, Cambridge, United Kingdom;1. Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France;2. Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France;3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;4. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands;5. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;6. Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;7. Genetic Department, Dubai Health Authority, Latifa Women and Children Hospital, Dubai, United Arab Emirates;8. Dubai Genetics Center, Pathology and Genetics Department, Dubai Health Authority, Dubai, United Arab Emirates;9. Department of Clinical Genetics & Human Genetics, Odense University Hospital, University of Southern Denmark, Odense, Denmark;10. Department of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark;11. Department of Pediatric, Division of Medical Genetics, Stanford University and Health Care, Palo Alto, CA;12. Center for Human Genetics, University Hospital Leuven, KU Leuven, O&N I Herestraat 49, Leuven, Belgium;13. University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands;14. Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA;15. Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA;16. Department of Clinical and Molecular Genetics, Hospital Vall d''Hebron, Barcelona, Spain;17. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain;18. AiLife Diagnostics, Pearland, TX;19. Clinical Genetics and Neurodevelopmental Disorders, Centre Hospitalier de l''Estran, Pontorson, France;20. Department of Medical Genetics, Toulouse University Hospital, Toulouse, France;21. Centre de référence Anomalies du Développement et Syndromes malformatifs, FHU-TRANSLAD, GAD, CHU Dijon et Université de Bourgogne, Dijon, France;22. Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France;23. Inserm UMR1231, GAD, Université de Bourgogne, Dijon, France;1. Department of Health and Kinesiology, Texas A&M University, College Station, TX;2. College of Nursing, Texas A&M University, College Station, TX;3. Department of Nutrition, Texas A&M University, College Station, TX;4. School of Public Health, Texas A&M University, College Station, TX;5. Jeb E. Brooks School of Public Policy, Cornell University, Ithaca, NY;6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;7. College of Nursing, Texas A&M University, McAllen, TX;1. Department of Medical Genetics, Reference Centre for Rare Diseases, Developmental Anomalies and Malformation Syndromes Sud-Est, Clermont-Ferrand University Hospital, Clermont-Ferrand, France;2. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada;3. Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences and Saint Joseph’s Healthcare, London, Ontario, Canada;4. Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;5. Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC;6. Medical Genetic Department for Rare Diseases and Personalized Medicine, Montpellier University Hospital, Montpellier, France;7. Clinical Genetics Department, Poitiers University Hospital, Poitiers, France;8. Clinical genetic department, Righospitalet, Copenhagen, Denmark;9. Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark;10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;11. Medical Genetics Department, Bretagne-Atlantique Hospital, Vannes, France;12. Department of Molecular Genetics and Genomics, Rennes University Hospital, Rennes, France;13. Univ Rennes, CNRS, IGDR, UMR 6290, Rennes, France;14. Department of Clinical Genetics, Reference Centre for Rare Diseases, CLAD Ouest, Rennes University Hospital, Rennes, France;15. Texas Children''s Hospital, Houston, TX;16. Department of Medical Genetics, Oslo University Hospitals and University of Oslo, Oslo, Norway;17. Departments of Neurosciences and Pediatrics, University of California San Diego, San Diego, CA;18. Division of Neurology, Rady Children’s Hospital, San Diego, CA;19. Rady Children’s Institute for Genomic Medicine, Rady Children’s Hospital, San Diego, CA;20. Medical Genetics Laboratory, ASST Papa Giovanni XXIII, Bergamo, Italy;21. Department of Medical Genetics, Women Mother Children Hospital, Hospices Civils de Lyon, Lyon, France;22. Department of Medical Genetics, Reference Center for Developmental Anomalies, CLAD Ouest, Rennes University Hospital, ERN ITHACA, CNRS UMR 6290, Genetics and Development Institute, Rennes University, Rennes, France;23. Functional Unit of Innovative Diagnosis for Rare Diseases, Dijon Bourgogne University Hospital, Dijon, France;24. Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy;25. Division of Pediatric and Adolescent Medicine, Oslo University Hospital, and University of Oslo, Oslo, Norway;26. Department of Neurology, University of Utah, Salt Lake City, UT;1. Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada;2. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada;3. Division of Neonatology, Department of Paediatrics, University of British Columbia, Vancouver, British Columbia, Canada;4. Centre for Health Evaluation and Outcome Sciences, St. Paul’s Hospital, Vancouver, British Columbia, Canada;1. Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Edegem, Belgium;2. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland;3. Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland;4. Centre de Référence Malformations et Maladies Congénitales du Cervelet et Déficiences Intellectuelles de Causes Rares, Département de Génétique et Embryologie Médicale, Hôpital Trousseau, Sorbonne Université, AP-HP, Paris, France;5. HudsonAlpha Institute for Biotechnology, Huntsville, AL;6. Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Lausanne, Switzerland;7. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;8. Biochemistry and Genetics Department, University Hospital of Angers, Angers, France;9. Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium;10. Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium;11. Applied and Translational Neurogenomics, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium;12. Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, NY;13. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN;14. Autism Brain & Behavior Laboratory, Department Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland;15. Ludwig Institute for Cancer Research, Department of Fundamental Oncology, Faculty of Biology and Medicine, Lausanne University, Epalinges, Lausanne, Switzerland;16. Medical Genetics, Sanford Broadway Clinic, Fargo, ND;17. Department of Genetics, AP-HP, La Pitié-Salpêtrière Hospital, Sorbonne Université, Paris;18. Neuropédiatrie, AP-HP, Hôpital d’enfants Armand Trousseau, Sorbonne Université, Paris;19. NYU Langone Medical Center, New York, NY;20. GeneDx, Gaithersburg, MD;21. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO;22. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;23. Institute of Human Genetics, Technical University München, Munich, Germany;24. Institute for Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany;25. Service de Génétique Médicale, Institut de Génétique Médicale d’Alsace, Hopitaux Universitaires de Strasbourg, Strasbourg, France;26. Laboratoires de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace, Hopitaux Universitaires de Strasbourg, Strasbourg, France;27. Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;28. Medical Genetics, Department of Pediatrics, University of Massachusetts Medical School-Baystate, Springfield, MA
Abstract:PurposeGenome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes.MethodsClinical data was collected through an extensive web-based survey.ResultsWe included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%).ConclusionOur data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.
Keywords:BAF-complex  Fetal
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