. 2021 Nov;23(11):2150-2159.

doi: 10.1038/s41436-021-01263-1. Epub 2021 Aug 3.

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Jérémie Courraud^{1

2

3

4}, Eric Chater-Diehl⁵, Benjamin Durand^{1

2

3

4}, Marie Vincent⁶, Maria Del Mar Muniz Moreno^{1

2

3

4}, Imene Boujelbene^{1

2

3

4

7}, Nathalie Drouot^{1

2

3

4}, Loréline Genschik^{1

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 Denommé^{18

19}, Laurence Faivre¹⁸, Claire Feger⁷, Mélanie Fradin²⁰, Christine Francannet²¹, David Genevieve¹⁴, Alice Goldenberg²², Anne-Marie Guerrot²², Bertrand Isidor⁶, Katrine M Johannesen^{23

24}, Boris Keren¹³, Maria Kibæk²⁵, Paul Kuentz¹⁸, Michèle Mathieu-Dramard²⁶, Bénédicte Demeer²⁶, Julia Metreau²⁷, Rikke Steensbjerre Møller^{23

24}, Sébastien Moutton¹⁸, Laurent Pasquier²⁰, Kristina Pilekær Sørensen²⁵, Laurence Perrin²⁸, Mathilde Renaud²⁹, Pascale Saugier²², Marlène Rio³⁰, Joane Svane²⁵, Julien Thevenon³¹, Frédéric Tran Mau Them^{18

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 Herault^{1

2

3

4}, Julie Thompson³⁹, Marjolaine Willems¹⁴, Jean-Louis Mandel^{1

2

3

4}, Rosanna Weksberg^{5

40

41

42

43}, Amélie Piton^{44

45

46

47

48

49}

Affiliations

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.

PMID: 34345024
DOI: 10.1038/s41436-021-01263-1

Free article

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Jérémie Courraud et al. Genet Med. 2021 Nov.

Free article

. 2021 Nov;23(11):2150-2159.

doi: 10.1038/s41436-021-01263-1. Epub 2021 Aug 3.

Authors

Affiliations

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.

PMID: 34345024
DOI: 10.1038/s41436-021-01263-1

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.

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Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

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Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

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