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DOI 10.1038/s41436-021-01263-1

Медицинская библиотека · Genetics in medicine : official journal of the American College of Medical Genetics · 2021

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

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

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Аннотация

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.

Для цитирования: 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. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder.. Genetics in medicine : official journal of the American College of Medical Genetics. 2021. DOI: 10.1038/s41436-021-01263-1.

Предметные рубрики MeSH

AnimalsHumansIntellectual DisabilityMiceMicrocephalyPhenotypeProtein Serine-Threonine KinasesProtein-Tyrosine KinasesDyrk Kinases
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