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

Jeremie Courraud 1, 2 Eric Chater-Diehl 3 Benjamin Durand 1, 2 Marie Vincent 4 Maria del Mar Muniz Moreno 1, 2 Imène Boujelbene 2 Nathalie Drouot 1, 2 Lauréline Genschik 2 Elise Schaefer 5 Mathilde Nizon 4 Bénédicte Gerard 6 Marc Abramowicz Benjamin Cogné 4 Lucas Bronicki Lydie Burglen Magalie Barth Perrine Charles Estelle Colin Christine Coubes Albert David 4 Bruno Delobel Florence Demurger Sandrine Passemard Anne-Sophie Denommé 7 Laurence Faivre 7 Claire Feger Melanie Fradin 8 Christine Francannet David Genevieve Alice Goldenberg 9 Anne-Marie Guerrot 9 Bertrand Isidor 4 Katrine M. Johannesen Boris Keren Maria Kibæk Paul Kuentz 7 Michele Mathieu-Dramard Bénédicte Demeer Julia Metreau Rikke Steensbjerre Møller Sébastien Moutton 7 Laurent Pasquier 8 Kristina Pilekær Sørensen Laurence Perrin Mathilde Renaud Pascale Saugier 9 Marlene Rio 10 Joane Svane Julien Thevenon Frederic Tran Mau Them Cathrine Elisabeth Tronhjem Antonio Vitobello Valerie Layet Marie-Christine Birling 1, 2 Severine Drunat Allan Bayat Christèle Dubourg 11, 8 Salima El Chehadeh Christina Fagerberg Cyril Mignot Michel Guipponi Thierry Bienvenu 12 Yann Herault 1, 2 Julie Thompson 13 Marjolaine Willems 14 Jean-Louis Mandel 1, 2 Rosanna Weksberg 15 Amelie Piton 1, 2, 16, *
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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Submitted on : Wednesday, November 10, 2021 - 5:01:21 PM
Last modification on : Wednesday, December 1, 2021 - 3:32:13 PM


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Jeremie Courraud, Eric Chater-Diehl, Benjamin Durand, Marie Vincent, Maria del Mar Muniz Moreno, et al.. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder. Genetics in Medicine, Nature Publishing Group, 2021, 23, pp.2150-2159. ⟨10.1038/s41436-021-01263-1⟩. ⟨hal-03269307⟩



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