Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder
Author:
Courraud Jeremie, Chater-Diehl Eric, Durand Benjamin, Vincent Marie, del Mar Muniz Moreno Maria, Boujelbene Imène, Drouot Nathalie, Genschik Loréline, Schaefer Elise, Nizon Mathilde, Gerard Bénédicte, Abramowicz Marc, Cogné Benjamin, Bronicki Lucas, Burglen Lydie, Barth Magalie, Charles Perrine, Colin Estelle, Coubes Christine, David Albert, Delobel Bruno, Demurger Florence, Passemard Sandrine, Denommé Anne-Sophie, Faivre Laurence, Feger Claire, Fradin Mélanie, Francannet Christine, Genevieve David, Goldenberg Alice, Guerrot Anne-Marie, Isidor Bertrand, Johannesen Katrine M.ORCID, Keren Boris, Kibæk Maria, Kuentz Paul, Mathieu-Dramard Michele, Demeer Bénédicte, Metreau Julia, Møller Rikke SteensbjerreORCID, Moutton Sébastien, Pasquier Laurent, Pilekær Sørensen Kristina, Perrin Laurence, Renaud Mathilde, Saugier Pascale, Svane Joane, Thevenon Julien, Them Frederic Tran Mau, Tronhjem Cathrine Elisabeth, Vitobello Antonio, Layet Valerie, Birling Marie-Christine, Drunat Severine, Bayat Allan, Dubourg Christèle, Chehadeh Salima El, Fagerberg Christina, Mignot Cyril, Guipponi Michel, Bienvenu Thierry, Herault Yann, Thompson Julie, Willems MarjolaineORCID, Mandel Jean-Louis, Weksberg Rosanna, Piton Amélie
Abstract
ABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboringDYRK1Avariants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specificDYRK1Aclinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii)in vitrooverexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) 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, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurringde novo.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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