Jérémie Courraud1,2,3,4, Eric Chater-Diehl5, Benjamin Durand1,2,3,4, Marie Vincent6, Maria Del Mar Muniz Moreno1,2,3,4, Imene Boujelbene1,2,3,4,7, Nathalie Drouot1,2,3,4, Loréline Genschik1,2,3,4, Elise Schaefer8, Mathilde Nizon6, Bénédicte Gerard7, Marc Abramowicz9, Benjamin Cogné6, Lucas Bronicki10, Lydie Burglen11, Magalie Barth12, Perrine Charles13, Estelle Colin12, Christine Coubes14, Albert David6, Bruno Delobel15, Florence Demurger16, Sandrine Passemard17, Anne-Sophie Denommé18,19, Laurence Faivre18, Claire Feger7, Mélanie Fradin20, Christine Francannet21, David Genevieve14, Alice Goldenberg22, Anne-Marie Guerrot22, Bertrand Isidor6, Katrine M Johannesen23,24, Boris Keren13, Maria Kibæk25, Paul Kuentz18, Michèle Mathieu-Dramard26, Bénédicte Demeer26, Julia Metreau27, Rikke Steensbjerre Møller23,24, Sébastien Moutton18, Laurent Pasquier20, Kristina Pilekær Sørensen25, Laurence Perrin28, Mathilde Renaud29, Pascale Saugier22, Marlène Rio30, Joane Svane25, Julien Thevenon31, Frédéric Tran Mau Them18,19, Cathrine Elisabeth Tronhjem25, Antonio Vitobello18, Valérie Layet32, Stéphane Auvin33, Khaoula Khachnaoui34, Marie-Christine Birling35, Séverine Drunat36, Allan Bayat25, Christèle Dubourg37, Salima El Chehadeh7, Christina Fagerberg25, Cyril Mignot12, Michel Guipponi9, Thierry Bienvenu38, Yann Herault1,2,3,4, Julie Thompson39, Marjolaine Willems14, Jean-Louis Mandel1,2,3,4, Rosanna Weksberg5,40,41,42,43, Amélie Piton44,45,46,47,48,49. 1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. 2. Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. 3. Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. 4. Université de Strasbourg, Illkirch, France. 5. Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. 6. Service de Génétique Médicale, CHU de Nantes & Inserm, CNRS, Université de Nantes, l'institut du thorax, Nantes, France. 7. Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France. 8. Service de Génétique Médicale, IGMA, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 9. Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. 10. Department of Genetics, CHEO, Ottawa, ON, Canada. 11. Centre de référence des malformations et maladies congénitales du cervelet et Département de génétique et embryologie médicale, APHP, Sorbonne Université, Hôpital Armand Trousseau, Paris, France. 12. Pediatrics & Biochemistry and Genetics, Department, Angers Hospital, Angers, France. 13. Genetic Department, University Hospital Pitié-Salpêtrière, AP-HP, Paris, France. 14. Département de Génétique Médicale maladies rares et médecine personnalisée, Centre de Référence Maladies Rares Anomalies du Développement, Hôpital Arnaud de Villeneuve, Université Montpellier, Montpellier, France. 15. Centre de Génétique Chromosomique, GHICL, Hôpital Saint Vincent de Paul, Lille, France. 16. Service de Génétique, CH Bretagne Atlantique-Vannes, Vannes, France. 17. Département de Génétique, Hôpital Universitaire Robert Debré, APHP, Paris, France. 18. Centre de Génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants and INSERM UMR1231 GAD, FHU TRANSLAD, CHU de Dijon, Dijon, France. 19. Unité Fonctionnelle d'Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France. 20. Centre de Référence Maladies Rares, Unité Fonctionnelle de Génétique Médicale, CHU, Rennes, France. 21. Service de Génétique médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France. 22. Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France. 23. Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre, Dianalund, Denmark. 24. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 25. Department of Clinical Genetics, Odense Denmark Hospital, Odense University Hospital, Odense, Denmark. 26. Service de Génétique Clinique, Centre de référence maladies rares, CHU d'Amiens-site Sud, Amiens, France. 27. APHP, Service de neurologie pédiatrique, Hôpital Universitaire Bicetre, Le Kremlin-Bicetre, France. 28. Department of Genetics, Robert Debré Hospital, AP-HP, Paris, France. 29. Service de Génétique Clinique et de Neurologie, Hôpital Brabois Enfants, Nancy, France. 30. Department of medical genetics and reference centre for rare intellectual disabilities, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Necker Enfants Malades Hospital, Paris, France. 31. Department of Genetics and Reproduction, Centre Hospitalo-Universitaire Grenoble-Alpes, Grenoble, France. 32. Consultations de génétique, Groupe Hospitalier du Havre, Le Havre, France. 33. Center for rare epilepsies & epilepsy unit Robert-Debré Hospital, APHP, & INSERM NeuroDiderot, Université de Paris, Paris, France. 34. Université Côte d'Azur, Inserm U1081, CNRS UMR7284, IRCAN, CHU de Nice, Nice, France. 35. ICS, Mouse Clinical Institute, Illkirch-Graffenstaden, France. 36. Département de Génétique, Hôpital Universitaire Robert Debré, Paris, France. 37. Laboratoire de Génétique Moléculaire, CHU Pontchaillou, UMR 6290 CNRS, IGDR, Faculté de Médecine, Université de Rennes 1, Rennes, France. 38. Molecular Genetics Laboratory, Cochin Hospital, APHP.Centre-Université de Paris, and INSERM UMR 1266, Institut de Psychiatrie et de Neurosciences de Paris, Paris, France. 39. Complex Systems and Translational Bioinformatics (CSTB), ICube laboratory-CNRS, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, Strasbourg, France. 40. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. 41. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. 42. Department of Pediatrics, University of Toronto, Toronto, ON, Canada. 43. Institute of Medical Science, School of Graduate Studies, University of Toronto, Toronto, ON, Canada. 44. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. piton@igbmc.fr. 45. Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. piton@igbmc.fr. 46. Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. piton@igbmc.fr. 47. Université de Strasbourg, Illkirch, France. piton@igbmc.fr. 48. Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France. piton@igbmc.fr. 49. Institut Universitaire de France, Paris, France. piton@igbmc.fr.
Abstract
PURPOSE: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics. METHODS: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature. RESULTS: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice. CONCLUSION: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene.
PURPOSE: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics. METHODS: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature. RESULTS: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice. CONCLUSION: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene.
Authors: Lucas M Bronicki; Claire Redin; Severine Drunat; Amélie Piton; Michael Lyons; Sandrine Passemard; Clarisse Baumann; Laurence Faivre; Julien Thevenon; Jean-Baptiste Rivière; Bertrand Isidor; Grace Gan; Christine Francannet; Marjolaine Willems; Murat Gunel; Julie R Jones; Joseph G Gleeson; Jean-Louis Mandel; Roger E Stevenson; Michael J Friez; Arthur S Aylsworth Journal: Eur J Hum Genet Date: 2015-04-29 Impact factor: 4.246
Authors: Jianling Ji; Hane Lee; Bob Argiropoulos; Naghmeh Dorrani; John Mann; Julian A Martinez-Agosto; Natalia Gomez-Ospina; Natalie Gallant; Jonathan A Bernstein; Louanne Hudgins; Leah Slattery; Bertrand Isidor; Cédric Le Caignec; Albert David; Ewa Obersztyn; Barbara Wiśniowiecka-Kowalnik; Michelle Fox; Joshua L Deignan; Eric Vilain; Emily Hendricks; Margaret Horton Harr; Sarah E Noon; Jessi R Jackson; Alisha Wilkens; Ghayda Mirzaa; Noriko Salamon; Jeff Abramson; Elaine H Zackai; Ian Krantz; A Micheil Innes; Stanley F Nelson; Wayne W Grody; Fabiola Quintero-Rivera Journal: Eur J Hum Genet Date: 2015-05-06 Impact factor: 4.246
Authors: S Himpel; P Panzer; K Eirmbter; H Czajkowska; M Sayed; L C Packman; T Blundell; H Kentrup; J Grötzinger; H G Joost; W Becker Journal: Biochem J Date: 2001-11-01 Impact factor: 3.857
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Authors: Aidin Foroutan; Sadegheh Haghshenas; Pratibha Bhai; Michael A Levy; Jennifer Kerkhof; Haley McConkey; Marcello Niceta; Andrea Ciolfi; Lucia Pedace; Evelina Miele; David Genevieve; Solveig Heide; Mariëlle Alders; Giuseppe Zampino; Giuseppe Merla; Mélanie Fradin; Eric Bieth; Dominique Bonneau; Klaus Dieterich; Patricia Fergelot; Elise Schaefer; Laurence Faivre; Antonio Vitobello; Silvia Maitz; Rita Fischetto; Cristina Gervasini; Maria Piccione; Ingrid van de Laar; Marco Tartaglia; Bekim Sadikovic; Anne-Sophie Lebre Journal: Int J Mol Sci Date: 2022-02-05 Impact factor: 5.923