Portal de Periódicos da CAPES

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

2021; Elsevier BV; Volume: 23; Issue: 11 Linguagem: Inglês

10.1038/s41436-021-01263-1

1530-0366

Jérémie Courraud, Eric Chater‐Diehl, Benjamin Durand, Marie Vincent, Maria del Mar Muñiz Moreno, I. Boujelbene, Nathalie Drouot, Loréline Genschik, Élise Schaefer, Mathilde Nizon, Bénédicte Gerard, Marc Abramowicz, Benjamin Cogné, Lucas Bronicki, Lydie Bürglen, Magalie Barth, Perrine Charles, Estelle Colin, Christine Coubes, Albert David, Bruno Delobel, Florence Démurger, Sandrine Passemard, Anne‐Sophie Denommé‐Pichon, Laurence Faivre, Claire Feger, Mélanie Fradin, Christine Francannet, David Geneviève, Alice Goldenberg, Anne-Marie Guerrot, Bertrand Isidor, Katrine M. Johannesen, Boris Keren, Maria Kibæk, Paul Kuentz, Michèle Mathieu-Dramard, Bénédicte Demeer, Julia Métreau, Rikke S. Møller, Sébastien Moutton, Laurent Pasquier, Kristina P. Sørensen, Laurence Perrin, Mathilde Renaud, Pascale Saugier‐Veber, Marlène Rio, Joane Svane, Julien Thévenon, 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 Hérault, Julie Thompson, Marjolaine Willems, Jean-Louis Mandel, Rosanna Weksberg, Amélie Piton,

Autism Spectrum Disorder Research

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.