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 David; Bruno 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

doi:10.1038/s41436-021-01263-1

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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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

Originalsprog	Engelsk
Tidsskrift	Genetics in Medicine
Vol/bind	23
Udgave nummer	11
Sider (fra-til)	2150-2159
ISSN	1098-3600
DOI	https://doi.org/10.1038/s41436-021-01263-1
Status	Udgivet - 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.

Dokumenter og links

10.1038/s41436-021-01263-1

https://hal.archives-ouvertes.fr/hal-03269307/file/Courraud%20et%20al%20-%202021%20-%20Integrative%20approach%20to%20interpret%20DYRK1A%20variants.pdf

SDU link

Tjek adgangen til materialet i Syddansk Universitetsbiblioteks søgemaskine

Citationsformater

Courraud, J., Chater-Diehl, E., Durand, B., Vincent, M., del Mar Muniz Moreno, M., Boujelbene, I., Drouot, N., Genschik, L., Schaefer, E., Nizon, M., Gerard, B., Abramowicz, M., Cogné, B., Bronicki, L., Burglen, L., Barth, M., Charles, P., Colin, E., Coubes, C., ... Piton, A. (2021). Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder. Genetics in Medicine, 23(11), 2150-2159. https://doi.org/10.1038/s41436-021-01263-1

@article{f27076a3a78042ad860267e89bf80eec,

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

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

author = "J{\'e}r{\'e}mie Courraud and Eric Chater-Diehl and Benjamin Durand and Marie Vincent and \{del Mar Muniz Moreno\}, Maria and Imene Boujelbene and Nathalie Drouot and Lor{\'e}line Genschik and Elise Schaefer and Mathilde Nizon and B{\'e}n{\'e}dicte Gerard and Marc Abramowicz and Benjamin Cogn{\'e} and Lucas Bronicki and Lydie Burglen and Magalie Barth and Perrine Charles and Estelle Colin and Christine Coubes and Albert David and Bruno Delobel and Florence Demurger and Sandrine Passemard and Denomm{\'e}, \{Anne Sophie\} and Laurence Faivre and Claire Feger and M{\'e}lanie Fradin and Christine Francannet and David Genevieve and Alice Goldenberg and Guerrot, \{Anne Marie\} and Bertrand Isidor and Johannesen, \{Katrine M.\} and Boris Keren and Maria Kib{\ae}k and Paul Kuentz and Mich{\`e}le Mathieu-Dramard and B{\'e}n{\'e}dicte Demeer and Julia Metreau and \{Steensbjerre M{\o}ller\}, Rikke and S{\'e}bastien Moutton and Laurent Pasquier and \{Pilek{\ae}r S{\o}rensen\}, Kristina and Laurence Perrin and Mathilde Renaud and Pascale Saugier and Marl{\`e}ne Rio and Joane Svane and Julien Thevenon and \{Tran Mau Them\}, Fr{\'e}d{\'e}ric and Tronhjem, \{Cathrine Elisabeth\} and Antonio Vitobello and Val{\'e}rie Layet and St{\'e}phane Auvin and Khaoula Khachnaoui and Birling, \{Marie Christine\} and S{\'e}verine Drunat and Allan Bayat and Christ{\`e}le Dubourg and \{El Chehadeh\}, Salima and Christina Fagerberg and Cyril Mignot and Michel Guipponi and Thierry Bienvenu and Yann Herault and Julie Thompson and Marjolaine Willems and Mandel, \{Jean Louis\} and Rosanna Weksberg and Am{\'e}lie Piton",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.",

year = "2021",

month = nov,

doi = "10.1038/s41436-021-01263-1",

language = "English",

volume = "23",

pages = "2150--2159",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier",

number = "11",

}

Courraud, J, Chater-Diehl, E, Durand, B, Vincent, M, del Mar Muniz Moreno, M, Boujelbene, I, Drouot, N, Genschik, L, Schaefer, E, Nizon, M, Gerard, B, Abramowicz, M, Cogné, B, Bronicki, L, Burglen, L, Barth, M, Charles, P, Colin, E, Coubes, C, David, A, Delobel, B, Demurger, F, Passemard, S, Denommé, AS, Faivre, L, Feger, C, Fradin, M, Francannet, C, Genevieve, D, Goldenberg, A, Guerrot, AM, Isidor, B, Johannesen, KM, Keren, B, Kibæk, M, Kuentz, P, Mathieu-Dramard, M, Demeer, B, Metreau, J, Steensbjerre Møller, R, Moutton, S, Pasquier, L, Pilekær Sørensen, K, Perrin, L, Renaud, M, Saugier, P, Rio, M, Svane, J, Thevenon, J, Tran Mau Them, F, Tronhjem, CE, Vitobello, A, Layet, V, Auvin, S, Khachnaoui, K, Birling, MC, Drunat, S, Bayat, A, Dubourg, C, El Chehadeh, S, Fagerberg, C, Mignot, C, Guipponi, M, Bienvenu, T, Herault, Y, Thompson, J, Willems, M, Mandel, JL, Weksberg, R & Piton, A 2021, 'Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder', Genetics in Medicine, bind 23, nr. 11, s. 2150-2159. https://doi.org/10.1038/s41436-021-01263-1

TY - JOUR

T1 - Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

AU - Courraud, Jérémie

AU - Chater-Diehl, Eric

AU - Durand, Benjamin

AU - Vincent, Marie

AU - del Mar Muniz Moreno, Maria

AU - Boujelbene, Imene

AU - Drouot, Nathalie

AU - Genschik, Loréline

AU - Schaefer, Elise

AU - Nizon, Mathilde

AU - Gerard, Bénédicte

AU - Abramowicz, Marc

AU - Cogné, Benjamin

AU - Bronicki, Lucas

AU - Burglen, Lydie

AU - Barth, Magalie

AU - Charles, Perrine

AU - Colin, Estelle

AU - Coubes, Christine

AU - David, Albert

AU - Delobel, Bruno

AU - Demurger, Florence

AU - Passemard, Sandrine

AU - Denommé, Anne Sophie

AU - Faivre, Laurence

AU - Feger, Claire

AU - Fradin, Mélanie

AU - Francannet, Christine

AU - Genevieve, David

AU - Goldenberg, Alice

AU - Guerrot, Anne Marie

AU - Isidor, Bertrand

AU - Johannesen, Katrine M.

AU - Keren, Boris

AU - Kibæk, Maria

AU - Kuentz, Paul

AU - Mathieu-Dramard, Michèle

AU - Demeer, Bénédicte

AU - Metreau, Julia

AU - Steensbjerre Møller, Rikke

AU - Moutton, Sébastien

AU - Pasquier, Laurent

AU - Pilekær Sørensen, Kristina

AU - Perrin, Laurence

AU - Renaud, Mathilde

AU - Saugier, Pascale

AU - Rio, Marlène

AU - Svane, Joane

AU - Thevenon, Julien

AU - Tran Mau Them, Frédéric

AU - Tronhjem, Cathrine Elisabeth

AU - Vitobello, Antonio

AU - Layet, Valérie

AU - Auvin, Stéphane

AU - Khachnaoui, Khaoula

AU - Birling, Marie Christine

AU - Drunat, Séverine

AU - Bayat, Allan

AU - Dubourg, Christèle

AU - El Chehadeh, Salima

AU - Fagerberg, Christina

AU - Mignot, Cyril

AU - Guipponi, Michel

AU - Bienvenu, Thierry

AU - Herault, Yann

AU - Thompson, Julie

AU - Willems, Marjolaine

AU - Mandel, Jean Louis

AU - Weksberg, Rosanna

AU - Piton, Amélie

PY - 2021/11

Y1 - 2021/11

N2 - 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.]

AB - 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.]

U2 - 10.1038/s41436-021-01263-1

DO - 10.1038/s41436-021-01263-1

M3 - Journal article

C2 - 34345024

AN - SCOPUS:85111872925

SN - 1098-3600

VL - 23

SP - 2150

EP - 2159

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

ER -

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

Abstract

Bibliografisk note

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