Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Courraud Jérémie, Chater-Diehl Eric, Durand Benjamin, Vincent Marie, Del Mar Muniz Moreno Maria, Boujelbene Imene, 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, Keren Boris, Kibæk Maria, Kuentz Paul, Mathieu-Dramard Michèle, Demeer Bénédicte, Metreau Julia, Steensbjerre Møller Rikke, Moutton Sébastien, Pasquier Laurent, Pilekær Sørensen Kristina, Perrin Laurence, Renaud Mathilde, Saugier Pascale, Rio Marlène, Svane Joane, Thevenon Julien, Tran Mau Them Frédéric, Tronhjem Cathrine Elisabeth, Vitobello Antonio, Layet Valérie, Auvin Stéphane, Khachnaoui Khaoula, Birling Marie-Christine, Drunat Séverine, Bayat Allan, Dubourg Christèle, El Chehadeh Salima, Fagerberg Christina, Mignot Cyril, Guipponi Michel, Bienvenu Thierry, Herault Yann, Thompson Julie, Willems Marjolaine, Mandel Jean-Louis, Weksberg Rosanna, Piton Amélie
Аннотация
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.