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

Jérémie Courraud; Eric Chater-Diehl; Benjamin Durand; Marie Vincent; Maria del Mar Muñiz Moreno; Imène Boujelbene; Nathalie Drouot; Lauréline Genschik; Elise Schaefer; Mathilde Nizon; Bénédicte Gerard; Marc Abramowicz; Benjamin Cogné; Lucas Bronicki; Lydie Burglen; Magalie Barth; Perrine Charles; Estelle Colin; Christine Coubes; Albert David; Bruno Delobel; Florence Demurger; Sandrine Passemard; Anne-Sophie Denommé-Pichon; Laurence Faivre; Claire Feger; Mélanie Fradin; Christine Francannet; David Genevieve; Alice Goldenberg; Anne-Marie Guerrot; Bertrand Isidor; Katrine M. Johannesen; Boris Keren; Maria Kibæk; Paul Kuentz; Michele Mathieu-Dramard; Bénédicte Demeer; Julia Metreau; Rikke Steensbjerre Møller; Sébastien Moutton; Laurent Pasquier; Kristina Pilekær Sørensen; Laurence Perrin; Mathilde Renaud; Pascale Saugier; Marlène Rio; Joane Svane; Julien Thevenon; Frédéric Tran Mau-Them; Cathrine Elisabeth Tronhjem; Antonio Vitobello; Valerie Layet; Stéphane Auvin; Khaoula Khachnaoui; Marie-Christine Birling; Séverine Drunat; Allan Bayat; Christèle Dubourg; Salima El Chehadeh; Christina Fagerberg; Cyril Mignot; Michel Guipponi; Thierry Bienvenu; Yann Herault; Julie Thompson; Marjolaine Willems; Jean-Louis Mandel; Rosanna Weksberg; Amelie Piton

doi:10.1038/s41436-021-01263-1

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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

Jérémie Courraud, Eric Chater-Diehl, Benjamin Durand, Marie Vincent, Maria del Mar Muñiz Moreno, Imène Boujelbene, Nathalie Drouot, Lauréline Genschik, Elise Schaefer, Mathilde Nizon, …

Genetics in Medicine, Vol.23(11)

11/2021

DOI: https://doi.org/10.1038/s41436-021-01263-1

PMID: 34345024

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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Title: Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder
Creators - without role: Jérémie Courraud - Université de Strasbourg
Eric Chater-Diehl - Hospital for Sick Children
Benjamin Durand - Centre National de la Recherche Scientifique
Marie Vincent - Nantes Université
Maria del Mar Muñiz Moreno - Inserm
Imène Boujelbene - Inserm
Nathalie Drouot - Institut de génétique et de biologie moléculaire et cellulaire
Lauréline Genschik - Institut de génétique et de biologie moléculaire et cellulaire
Elise Schaefer - Hôpitaux Universitaires de Strasbourg
Mathilde Nizon - Nantes Université
Bénédicte Gerard - Hôpitaux Universitaires de Strasbourg
Marc Abramowicz - University Hospital of Geneva
Benjamin Cogné - Centre Hospitalier Universitaire de Nantes
Lucas Bronicki - Agricultural Research Institute of Ontario
Lydie Burglen - Sorbonne Université
Magalie Barth - Université d'Angers
Perrine Charles - Sorbonne Université
Estelle Colin - Université d'Angers
Christine Coubes - Université de Montpellier
Albert David - Centre Hospitalier Universitaire de Nantes
Bruno Delobel - Hôpital Saint-Vincent-de-Paul
Florence Demurger - Centre hospitalier Bretagne Atlantique
Sandrine Passemard - Hôpital Robert-Debré
Anne-Sophie Denommé-Pichon - Equipe GAD (LNC - U1231)
Laurence Faivre - Inserm
Claire Feger - Hôpitaux Universitaires de Strasbourg
Mélanie Fradin - Génétique Médicale & Génomique Fonctionelle
Christine Francannet - Centre Hospitalier Universitaire de Clermont-Ferrand
David Genevieve - Hôpital Arnaud de Villeneuve
Alice Goldenberg - Université de Rouen Normandie
Anne-Marie Guerrot - Inserm
Bertrand Isidor - Centre Hospitalier Universitaire de Nantes
Katrine M. Johannesen - University of Southern Denmark
Boris Keren - Sorbonne Université
Maria Kibæk - Odense University Hospital
Paul Kuentz - Inserm
Michele Mathieu-Dramard - Centre Hospitalier Universitaire Amiens-Picardie
Bénédicte Demeer - Centre Hospitalier Universitaire Amiens-Picardie
Julia Metreau - Bicêtre Hospital
Rikke Steensbjerre Møller - University of Southern Denmark
Sébastien Moutton - Inserm
Laurent Pasquier - Génétique Médicale & Génomique Fonctionelle
Kristina Pilekær Sørensen - Institute of Forensic Medicine [Odense]
Laurence Perrin - Assistance Publique – Hôpitaux de Paris
Mathilde Renaud - Service de Génétique Clinique Pédiatrique [CHRU Nancy]
Pascale Saugier - Service de Génétique [CHU Rouen]
Marlène Rio - Université Paris Cité
Joane Svane - Odense University Hospital
Julien Thevenon - Centre Hospitalier Universitaire de Grenoble
Frédéric Tran Mau-Them - Equipe GAD (LNC - U1231)
Cathrine Elisabeth Tronhjem - Odense University Hospital
Antonio Vitobello - Hôpital d'Enfants
Valerie Layet - Groupe Hospitalier du Havre
Stéphane Auvin - Université Paris Cité
Khaoula Khachnaoui - Inserm
Marie-Christine Birling - Institut de génétique et de biologie moléculaire et cellulaire
Séverine Drunat - Hôpital Robert-Debré
Allan Bayat - Odense University Hospital
Christèle Dubourg - Centre National de la Recherche Scientifique
Salima El Chehadeh - Hôpitaux Universitaires de Strasbourg
Christina Fagerberg - Odense University Hospital
Cyril Mignot - Université d'Angers
Michel Guipponi - University Hospital of Geneva
Thierry Bienvenu - Hôpital Cochin
Yann Herault - Inserm
Julie Thompson - Université de Strasbourg
Marjolaine Willems - Hôpital Arnaud de Villeneuve
Jean-Louis Mandel - Institut de génétique et de biologie moléculaire et cellulaire
Rosanna Weksberg - University of Toronto
Amelie Piton - Institut Universitaire de France
Publication Details: Genetics in Medicine, Vol.23(11)
Grant note: Agence de Biomédecine, Fondation APLM, Fondation Maladies Rares and Fondation Jérome Lejeune
Identifiers: 9934001809311
Academic Unit: Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB; Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-03269307