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

Animals Humans Intellectual Disability / diagnosis Mice Microcephaly Phenotype Protein Serine-Threonine Kinases / genetics Protein-Tyrosine Kinases / genetics Dyrk Kinases

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
11 2021
Historique:
received: 26 01 2021
accepted: 15 06 2021
revised: 14 06 2021
pubmed: 5 8 2021
medline: 12 11 2021
entrez: 4 8 2021
Statut: ppublish

Résumé

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. 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. 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. 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.

Identifiants

DOI: 10.1038/s41436-021-01263-1 PMID: 34345024
pubmed: 34345024
doi: 10.1038/s41436-021-01263-1
pii: S1098-3600(21)05187-X
doi:

Substances chimiques

Protein-Tyrosine Kinases EC 2.7.10.1
Protein Serine-Threonine Kinases EC 2.7.11.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

2150-2159

Informations de copyright

© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Références

Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–8. https://doi.org/10.1038/nature21062
doi: 10.1038/nature21062
Gonzalez-Mantilla AJ, Moreno-De-Luca A, Ledbetter DH, Martin CL. A cross-disorder method to identify novel candidate genes for developmental brain disorders. JAMA Psychiatry. 2016;73:275–83. https://doi.org/10.1001/jamapsychiatry.2015.2692
doi: 10.1001/jamapsychiatry.2015.2692 pubmed: 26817790 pmcid: 5333489
Møller RS, Kübart S, Hoeltzenbein M, Heye B, Vogel I, Hansen CP, et al. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am J Hum Genet. 2008;82:1165–70. https://doi.org/10.1016/j.ajhg.2008.03.001
doi: 10.1016/j.ajhg.2008.03.001 pubmed: 18405873 pmcid: 2427221
Courcet J-B, Faivre L, Malzac P, Masurel-Paulet A, Lopez E, Callier P, et al. The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. J Med Genet. 2012;49:731–36.
doi: 10.1136/jmedgenet-2012-101251
van Bon BW, Coe BP, Bernier R, Green C, Gerdts J, Witherspoon K, et al. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Mol Psychiatry. 2016;21:126–132. https://doi.org/10.1038/mp.2015.5
doi: 10.1038/mp.2015.5 pubmed: 25707398
Bronicki LM, Redin C, Drunat S, Piton A, Lyons M, Passemard S, et al. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A. Eur J Hum Genet. 2015;23:1482–1487. https://doi.org/10.1038/ejhg.2015.29
doi: 10.1038/ejhg.2015.29 pubmed: 25920557 pmcid: 4613470
Ruaud L, Mignot C, Guët A, Ohl C, Nava C, Héron D, et al. DYRK1A mutations in two unrelated patients. Eur J Med Genet. 2015;58:168–174. https://doi.org/10.1016/j.ejmg.2014.12.014
doi: 10.1016/j.ejmg.2014.12.014 pubmed: 25641759
Ji J, Lee H, Argiropoulos B, Dorrani N, Mann J, Martinez-Agosto JA, et al. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur J Hum Genet. 2015;23:1473–1481. https://doi.org/10.1038/ejhg.2015.71
doi: 10.1038/ejhg.2015.71 pubmed: 25944381 pmcid: 4613469
Meissner LE, Macnamara EF, D’souza P, Yang J, Vezina G, Undiagnosed Diseases N. et al. DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature. Mol Genet Genomic Med. 2020;7:e1544. https://doi.org/10.1002/mgg3.1544
doi: 10.1002/mgg3.1544
O’roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012;338:1619–1622. https://doi.org/10.1126/science.1227764
doi: 10.1126/science.1227764 pubmed: 23160955 pmcid: 3528801
Earl RK, Turner TN, Mefford HC, Hudac CM, Gerdts J, Eichler EE, et al. Clinical phenotype of ASD-associated DYRK1A haploinsufficiency. Mol Autism. 2017;8:54. https://doi.org/10.1186/s13229-017-0173-5
doi: 10.1186/s13229-017-0173-5 pubmed: 29034068 pmcid: 5629761
Himpel S, Panzer P, Eirmbter K, Czajkowska H, Sayed M, Packman LC, et al. Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. Biochem J. 2001;359:497–505. https://doi.org/10.1042/0264-6021:3590497
doi: 10.1042/0264-6021:3590497 pubmed: 11672423 pmcid: 1222170
Hämmerle B, Elizalde C, Tejedor FJ. The spatio-temporal and subcellular expression of the candidate Down syndrome gene Mnb/Dyrk1A in the developing mouse brain suggests distinct sequential roles in neuronal development. Eur J Neurosci. 2008;27:1061–1074. https://doi.org/10.1111/j.1460-9568.2008.06092.x
doi: 10.1111/j.1460-9568.2008.06092.x pubmed: 18364031
Tejedor FJ, Hämmerle B. MNB/DYRK1A as a multiple regulator of neuronal development. FEBS J. 2011;278:223–235. https://doi.org/10.1111/j.1742-4658.2010.07954.x
doi: 10.1111/j.1742-4658.2010.07954.x pubmed: 21156027
Duchon A, Herault Y. DYRK1A, a dosage-sensitive gene involved in neurodevelopmental disorders, is a target for drug development in Down syndrome. Front Behav Neurosci. 2016;10:104. https://doi.org/10.3389/fnbeh.2016.00104
doi: 10.3389/fnbeh.2016.00104 pubmed: 27375444 pmcid: 4891327
Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, et al. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem J. 2001;355:609–615. https://doi.org/10.1042/bj3550609
doi: 10.1042/bj3550609 pubmed: 11311121 pmcid: 1221774
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424. https://doi.org/10.1038/gim.2015.30
doi: 10.1038/gim.2015.30 pubmed: 25741868 pmcid: 4544753
Choufani S, Cytrynbaum C, Chung BH, Turinsky AL, Grafodatskaya D, Chen YA, et al. NSD1 mutations generate a genome-wide DNA methylation signature. Nat Commun. 2015;6:10207. https://doi.org/10.1038/ncomms10207
doi: 10.1038/ncomms10207 pubmed: 26690673
Choufani S, Gibson WT, Turinsky AL, Chung B, Wang T, Garg K, et al. DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes. Am J Hum Genet. 2020;106:596–610. https://doi.org/10.1016/j.ajhg.2020.03.008
doi: 10.1016/j.ajhg.2020.03.008 pubmed: 32243864 pmcid: 7212265
Chater-Diehl E, Ejaz R, Cytrynbaum C, Siu MT, Turinsky A, Choufani S, et al. New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome. BMC Med Genomics. 2019;12:105. https://doi.org/10.1186/s12920-019-0555-y
doi: 10.1186/s12920-019-0555-y pubmed: 31288860 pmcid: 6617651
Aref-Eshghi E, Bend EG, Colaiacovo S, Caudle M, Chakrabarti R, Napier M, et al. Diagnostic utility of genome-wide DNA methylation testing in genetically unsolved individuals with suspected hereditary conditions. Am J Hum Genet. 2019;104:685–700. https://doi.org/10.1016/j.ajhg.2019.03.008
doi: 10.1016/j.ajhg.2019.03.008 pubmed: 30929737 pmcid: 6451739
Jang SM, Azebi S, Soubigou G, Muchardt C. DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1-mediated transcriptional repression. EMBO Rep. 2014;15:686–694. https://doi.org/10.15252/embr.201338356
doi: 10.15252/embr.201338356 pubmed: 24820035 pmcid: 4197879
Li S, Xu C, Fu Y, Lei PJ, Yao Y, Yang W, et al. DYRK1A interacts with histone acetyl transferase p300 and CBP and localizes to enhancers. Nucleic Acids Res. 2018;46:11202–11213. https://doi.org/10.1093/nar/gky754
doi: 10.1093/nar/gky754 pubmed: 30137413 pmcid: 6265467
Redin C, Gérard B, Lauer J, Herenger Y, Muller J, Quartier A, et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet. 2014;51:724–736. https://doi.org/10.1136/jmedgenet-2014-102554
doi: 10.1136/jmedgenet-2014-102554 pubmed: 25167861
Carion N, Briand A, Cuisset L, Pacot L, Afenjar A, Bienvenu T. Loss of the KH1 domain of FMR1 in humans due to a synonymous variant causes global developmental retardation. Gene. 2020;753:144793. https://doi.org/10.1016/j.gene.2020.144793
doi: 10.1016/j.gene.2020.144793 pubmed: 32446918
Nasser H, Vera L, Elmaleh-Bergès M, Steindl K, Letard P, Teissier N, et al. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects. J Med Genet. 2020;57:389–399. https://doi.org/10.1136/jmedgenet-2019-106474
doi: 10.1136/jmedgenet-2019-106474 pubmed: 32015000
Balak C, Benard M, Schaefer E, Iqbal S, Ramsey K, Ernoult-Lange M, et al. Rare de novo missense variants in RNA helicase DDX6 cause intellectual disability and dysmorphic features and lead to P-body defects and RNA dysregulation. Am J Hum Genet. 2019;105:509–525. https://doi.org/10.1016/j.ajhg.2019.07.010
doi: 10.1016/j.ajhg.2019.07.010 pubmed: 31422817 pmcid: 6731366
Quartier A, Chatrousse L, Redin C, Keime C, Haumesser N, Maglott-Roth A, et al. Genes and pathways regulated by androgens in human neural cells, potential candidates for the male excess in autism spectrum disorder. Biol Psychiatry. 2018;84:239–252. https://doi.org/10.1016/j.biopsych.2018.01.002
doi: 10.1016/j.biopsych.2018.01.002 pubmed: 29428674
Waterhouse AM, Procter JB, Martin DMA, Clamp M, Barton GJ. Jalview version 2-a multiple sequence alignment editor and analysis workbench. Bioinformatics. 2009;25:1189–1191. https://doi.org/10.1093/bioinformatics/btp033
doi: 10.1093/bioinformatics/btp033 pubmed: 19151095 pmcid: 2672624
Kress A, Lecompte O, Poch O, Thompson JD. PROBE: analysis and visualization of protein block-level evolution. Bioinformatics. 2018;34:3390–3392. https://doi.org/10.1093/bioinformatics/bty367
doi: 10.1093/bioinformatics/bty367 pubmed: 29741582
Mattioli F, Isidor B, Abdul-Rahman O, Gunter A, Huang L, Kumar R, et al. Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Hum Mol Genet. 2019;28:952–960. https://doi.org/10.1093/hmg/ddy391
doi: 10.1093/hmg/ddy391 pubmed: 30476144
Quartier A, Courraud J, Thi Ha T, McGillivray G, Isidor B, Rose K, et al. Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment. Hum Mutat. 2019;40:2021–2032. https://doi.org/10.1002/humu.23836
doi: 10.1002/humu.23836 pubmed: 31184401
Widowati EW, Ernst S, Hausmann R, Müller-Newen G, Becker W Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism. Biol Open. 2018;7. https://doi.org/10.1242/bio.032862
Lee K-S, Choi M, Kwon D-W, Kim D, Choi JM, Kim AK, et al. A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay. Sci Rep. 2020;10:9849. https://doi.org/10.1038/s41598-020-66750-y
doi: 10.1038/s41598-020-66750-y pubmed: 32555303 pmcid: 7299959
Blackburn ATM, Bekheirnia N, Uma VC, Corkins ME, Xu Y, Rosenfeld JA, et al. DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract. Genet Med. 2019;21:2755–2764. https://doi.org/10.1038/s41436-019-0576-0
doi: 10.1038/s41436-019-0576-0 pubmed: 31263215 pmcid: 6895419
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–315. https://doi.org/10.1038/ng.2892
doi: 10.1038/ng.2892 pubmed: 24487276 pmcid: 3992975
Arranz J, Balducci E, Arató K, Sánchez-Elexpuru G, Najas S, Parras A, et al. Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome. Neurobiol Dis. 2019;127:210–222. https://doi.org/10.1016/j.nbd.2019.02.022
doi: 10.1016/j.nbd.2019.02.022 pubmed: 30831192 pmcid: 6753933
Dang T, Duan WY, Yu B, Tong DL, Cheng C, Zhang YF, et al. Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development. Mol Psychiatry. 2018;23:747–758. https://doi.org/10.1038/mp.2016.253
doi: 10.1038/mp.2016.253 pubmed: 28167836
Lepagnol-Bestel A-M, Zvara A, Maussion G, Quignon F, Ngimbous B, Ramoz N, et al. DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome. Hum Mol Genet. 2009;18:1405–1414. https://doi.org/10.1093/hmg/ddp047
doi: 10.1093/hmg/ddp047 pubmed: 19218269

Auteurs

Jérémie Courraud (J)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.

Eric Chater-Diehl (E)

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Benjamin Durand (B)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.

Marie Vincent (M)

Service de Génétique Médicale, CHU de Nantes & Inserm, CNRS, Université de Nantes, l'institut du thorax, Nantes, France.

Maria Del Mar Muniz Moreno (M)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.

Imene Boujelbene (I)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.
Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France.

Nathalie Drouot (N)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.

Loréline Genschik (L)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.

Elise Schaefer (E)

Service de Génétique Médicale, IGMA, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Mathilde Nizon (M)

Service de Génétique Médicale, CHU de Nantes & Inserm, CNRS, Université de Nantes, l'institut du thorax, Nantes, France.

Bénédicte Gerard (B)

Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France.

Marc Abramowicz (M)

Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.

Benjamin Cogné (B)

Service de Génétique Médicale, CHU de Nantes & Inserm, CNRS, Université de Nantes, l'institut du thorax, Nantes, France.

Lucas Bronicki (L)

Department of Genetics, CHEO, Ottawa, ON, Canada.

Lydie Burglen (L)

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.

Magalie Barth (M)

Pediatrics & Biochemistry and Genetics, Department, Angers Hospital, Angers, France.

Perrine Charles (P)

Genetic Department, University Hospital Pitié-Salpêtrière, AP-HP, Paris, France.

Estelle Colin (E)

Pediatrics & Biochemistry and Genetics, Department, Angers Hospital, Angers, France.

Christine Coubes (C)

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.

Albert David (A)

Service de Génétique Médicale, CHU de Nantes & Inserm, CNRS, Université de Nantes, l'institut du thorax, Nantes, France.

Bruno Delobel (B)

Centre de Génétique Chromosomique, GHICL, Hôpital Saint Vincent de Paul, Lille, France.

Florence Demurger (F)

Service de Génétique, CH Bretagne Atlantique-Vannes, Vannes, France.

Sandrine Passemard (S)

Département de Génétique, Hôpital Universitaire Robert Debré, APHP, Paris, France.

Anne-Sophie Denommé (AS)

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.
Unité Fonctionnelle d'Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.

Laurence Faivre (L)

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.

Claire Feger (C)

Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France.

Mélanie Fradin (M)

Centre de Référence Maladies Rares, Unité Fonctionnelle de Génétique Médicale, CHU, Rennes, France.

Christine Francannet (C)

Service de Génétique médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France.

David Genevieve (D)

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.

Alice Goldenberg (A)

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.

Anne-Marie Guerrot (AM)

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.

Bertrand Isidor (B)

Service de Génétique Médicale, CHU de Nantes & Inserm, CNRS, Université de Nantes, l'institut du thorax, Nantes, France.

Katrine M Johannesen (KM)

Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre, Dianalund, Denmark.
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.

Boris Keren (B)

Genetic Department, University Hospital Pitié-Salpêtrière, AP-HP, Paris, France.

Maria Kibæk (M)

Department of Clinical Genetics, Odense Denmark Hospital, Odense University Hospital, Odense, Denmark.

Paul Kuentz (P)

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.

Michèle Mathieu-Dramard (M)

Service de Génétique Clinique, Centre de référence maladies rares, CHU d'Amiens-site Sud, Amiens, France.

Bénédicte Demeer (B)

Service de Génétique Clinique, Centre de référence maladies rares, CHU d'Amiens-site Sud, Amiens, France.

Julia Metreau (J)

APHP, Service de neurologie pédiatrique, Hôpital Universitaire Bicetre, Le Kremlin-Bicetre, France.

Rikke Steensbjerre Møller (R)

Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre, Dianalund, Denmark.
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.

Sébastien Moutton (S)

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.

Laurent Pasquier (L)

Centre de Référence Maladies Rares, Unité Fonctionnelle de Génétique Médicale, CHU, Rennes, France.

Kristina Pilekær Sørensen (K)

Department of Clinical Genetics, Odense Denmark Hospital, Odense University Hospital, Odense, Denmark.

Laurence Perrin (L)

Department of Genetics, Robert Debré Hospital, AP-HP, Paris, France.

Mathilde Renaud (M)

Service de Génétique Clinique et de Neurologie, Hôpital Brabois Enfants, Nancy, France.

Pascale Saugier (P)

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.

Marlène Rio (M)

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.

Joane Svane (J)

Department of Clinical Genetics, Odense Denmark Hospital, Odense University Hospital, Odense, Denmark.

Julien Thevenon (J)

Department of Genetics and Reproduction, Centre Hospitalo-Universitaire Grenoble-Alpes, Grenoble, France.

Frédéric Tran Mau Them (F)

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.
Unité Fonctionnelle d'Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.

Cathrine Elisabeth Tronhjem (CE)

Department of Clinical Genetics, Odense Denmark Hospital, Odense University Hospital, Odense, Denmark.

Antonio Vitobello (A)

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.

Valérie Layet (V)

Consultations de génétique, Groupe Hospitalier du Havre, Le Havre, France.

Stéphane Auvin (S)

Center for rare epilepsies & epilepsy unit Robert-Debré Hospital, APHP, & INSERM NeuroDiderot, Université de Paris, Paris, France.

Khaoula Khachnaoui (K)

Université Côte d'Azur, Inserm U1081, CNRS UMR7284, IRCAN, CHU de Nice, Nice, France.

Marie-Christine Birling (MC)

ICS, Mouse Clinical Institute, Illkirch-Graffenstaden, France.

Séverine Drunat (S)

Département de Génétique, Hôpital Universitaire Robert Debré, Paris, France.

Allan Bayat (A)

Department of Clinical Genetics, Odense Denmark Hospital, Odense University Hospital, Odense, Denmark.

Christèle Dubourg (C)

Laboratoire de Génétique Moléculaire, CHU Pontchaillou, UMR 6290 CNRS, IGDR, Faculté de Médecine, Université de Rennes 1, Rennes, France.

Salima El Chehadeh (S)

Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France.

Christina Fagerberg (C)

Department of Clinical Genetics, Odense Denmark Hospital, Odense University Hospital, Odense, Denmark.

Cyril Mignot (C)

Pediatrics & Biochemistry and Genetics, Department, Angers Hospital, Angers, France.

Michel Guipponi (M)

Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.

Thierry Bienvenu (T)

Molecular Genetics Laboratory, Cochin Hospital, APHP.Centre-Université de Paris, and INSERM UMR 1266, Institut de Psychiatrie et de Neurosciences de Paris, Paris, France.

Yann Herault (Y)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.

Julie Thompson (J)

Complex Systems and Translational Bioinformatics (CSTB), ICube laboratory-CNRS, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, Strasbourg, France.

Marjolaine Willems (M)

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.

Jean-Louis Mandel (JL)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.

Rosanna Weksberg (R)

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
Institute of Medical Science, School of Graduate Studies, University of Toronto, Toronto, ON, Canada.

Amélie Piton (A)

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. piton@igbmc.fr.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. piton@igbmc.fr.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. piton@igbmc.fr.
Université de Strasbourg, Illkirch, France. piton@igbmc.fr.
Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France. piton@igbmc.fr.
Institut Universitaire de France, Paris, France. piton@igbmc.fr.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Integrative approach to interpret DYRK1A...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Integrative approach to interpret DYRK1A...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Déficience intellectuelle › Integrative approach to interpret DYRK1A...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Integrative approach to interpret DYRK1A...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations du système nerveux › Malformations corticales › Malformations corticales du groupe I › Microcéphalie › Integrative approach to interpret DYRK1A...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Integrative approach to interpret DYRK1A...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Integrative approach to interpret DYRK1A...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Integrative approach to interpret DYRK1A...