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

Jérémie Courraud, Eric Chater-Diehl, Benjamin Durand, Marie Vincent, Maria del Mar Muniz Moreno, Imene Boujelbene, Nathalie Drouot, Loréline Genschik, Elise Schaefer, Mathilde Nizon, Bénédicte Gerard, Marc Abramowicz, Benjamin Cogné, Lucas Bronicki, Lydie Burglen, Magalie Barth, Perrine Charles, Estelle Colin, Christine Coubes, Albert DavidBruno Delobel, Florence Demurger, Sandrine Passemard, Anne Sophie Denommé, 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, Michèle 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, Valérie 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, Amélie Piton*

*Kontaktforfatter for dette arbejde

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Abstrakt

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. Graphic abstract: [Figure not available: see fulltext.]

OriginalsprogEngelsk
TidsskriftGenetics in Medicine
Vol/bind23
Udgave nummer11
Sider (fra-til)2150-2159
ISSN1098-3600
DOI
StatusUdgivet - nov. 2021

Bibliografisk note

Funding Information:
The authors thank the families for their participation and support. The authors also thank the Agence de Biomédecine, Fondation APLM, Fondation Maladies Rares and Fondation Jérome Lejeune for financial support. We also thank the Centre National de Génotypage, the diagnostic laboratories of Hôpitaux Universitaire de Strasbourg (HUS), clinical genetics residents, the GenomEast sequencing and the molecular biology platforms of IGBMC.

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

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