Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype |
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| Institution: | 1. Institute of Medical Genetics, University of Zürich, Schlieren-Zurich, Switzerland.;2. Department of Biology, Stanford University, Stanford, CA, USA.;3. Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.;4. Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.;5. Children’s Research Centre, University Children’s Hospital, Zurich, Switzerland.;6. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.;7. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.;8. Service d’Histologie-Embryologie-Cytogénétique, Unité d’Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France.;9. INSERM UMR 1163, Université de Paris, Imagine Institute, Paris, France.;10. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.;11. Faculté de médecine, Université de Namur, Namur, Belgium.;12. Center for Rare Childhood Disorders (C4RCD), Translational Genomics Research Institute, Phoenix, AZ, USA.;13. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.;14. Département de Biologie Moléculaire, Institut de Pathologie et de Génétique, Gosselies, Belgium.;15. Centre de Génétique Humaine, Université de Franche-Comté, CHU, Besançon, France.;16. Service de Neuropédiatrie, CHU, Besançon, France.;17. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.;18. Maternité Port-Royal, AP-HP, Hôpital Cochin, Paris, France.;19. Service de Génétique Médicale, Hôpital Pellegrin CHU, Bordeaux, France.;20. Department of Pediatrics, Section of Genetics, University of Colorado Anschutz Medical Campus, Denver, CO, USA.;21. Deventer Ziekenhuis, Deventer, the Netherlands.;22. Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.;23. Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.;24. UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR 1231 GAD, FHU-TRANSLAD, Unité Fonctionnelle D’Innovation en Diagnostique Génomique Des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France.;25. Centre de Référence Maladies Rares « Anomalies du Développement Et Syndrome Malformatifs » de L’Est, Hôpital D’Enfants, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.;26. Division of Genetics, Arnold Palmer Hospital, Orlando Health, Orlando, FL, USA.;27. Department of Pediatrics, Boston Children’s Hospital, Divisions of Newborn Medicine and Genetics and Genomics, Boston, MA, USA.;28. The Broad Institute of MIT and Harvard, Cambridge, MA, USA.;29. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.;30. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.;1. Institute of Medical Genetics, University of Zürich, Schlieren-Zurich, Switzerland.;2. Department of Biology, Stanford University, Stanford, CA, USA.;3. Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.;4. Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.;5. Children’s Research Centre, University Children’s Hospital, Zurich, Switzerland.;6. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.;7. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.;8. Service d’Histologie-Embryologie-Cytogénétique, Unité d’Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France.;9. INSERM UMR 1163, Université de Paris, Imagine Institute, Paris, France.;10. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.;11. Faculté de médecine, Université de Namur, Namur, Belgium.;12. Center for Rare Childhood Disorders (C4RCD), Translational Genomics Research Institute, Phoenix, AZ, USA.;13. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.;14. Département de Biologie Moléculaire, Institut de Pathologie et de Génétique, Gosselies, Belgium.;15. Centre de Génétique Humaine, Université de Franche-Comté, CHU, Besançon, France.;16. Service de Neuropédiatrie, CHU, Besançon, France.;17. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.;18. Maternité Port-Royal, AP-HP, Hôpital Cochin, Paris, France.;19. Service de Génétique Médicale, Hôpital Pellegrin CHU, Bordeaux, France.;20. Department of Pediatrics, Section of Genetics, University of Colorado Anschutz Medical Campus, Denver, CO, USA.;21. Deventer Ziekenhuis, Deventer, the Netherlands.;22. Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.;23. Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.;24. UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR 1231 GAD, FHU-TRANSLAD, Unité Fonctionnelle D’Innovation en Diagnostique Génomique Des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France.;25. Centre de Référence Maladies Rares « Anomalies du Développement Et Syndrome Malformatifs » de L’Est, Hôpital D’Enfants, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.;26. Division of Genetics, Arnold Palmer Hospital, Orlando Health, Orlando, FL, USA.;27. Department of Pediatrics, Boston Children’s Hospital, Divisions of Newborn Medicine and Genetics and Genomics, Boston, MA, USA.;28. The Broad Institute of MIT and Harvard, Cambridge, MA, USA.;29. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.;30. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland. |
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| Abstract: | PurposeDespite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood.MethodsWe collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro.ResultsThe core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants.ConclusionNSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype. |
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