De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

Audrey Schalk; Margot A. Cousin; Nikita R. Dsouza; Thomas D. Challman; Karen E. Wain; Zoe Powis; Kelly Minks; Aurélien Trimouille; Eulalie Lasseaux; Didier Lacombe; Chloé Angelini; Vincent Michaud; Julien Van-Gils; Nino Spataro; Anna Ruiz; Elizabeth Gabau; Elliot Stolerman; Camerun Washington; Ray Louie; Brendan C. Lanpher; Jennifer L. Kemppainen; Micheil Innes; Frank Kooy; Marije Meuwissen; Alice Goldenberg; Francois Lecoquierre; Gabriella Vera; Karin E.M. Diderich; Beth Sheidley; Christelle Moufawad El Achkar; Meredith Park; Fadi F. Hamdan; Jacques L. Michaud; Ann J. Lewis; Christiane Zweier; André Reis; Matias Wagner; Heike Weigand; Hubert Journel; Boris Keren; Sandrine Passemard; Cyril Mignot; Koen Van Gassen; Eva H. Brilstra; Gina Itzikowitz; Emily O'Heir; Jake Allen; Kirsten A. Donald; Bruce Richard Korf; Tammi Skelton; Michelle Thompson; Nathaniel H. Robin; Natasha L. Rudy; William B. Dobyns; Kimberly Foss; Yuri Alexander Zarate; Katherine A. Bosanko; Yves Alembik; Benjamin Durand; Frederic Tran Mau-Them; Emmanuelle Ranza; Xavier Blanc; Stylianos E. Antonarakis; Kirsty McWalter; Erin Torti; Francisca Millan; Amy Dameron; Mari Tokita; Michael T. Zimmermann; Eric W Klee; Amelie Piton; Benedicte Gerard

doi:10.1136/jmedgenet-2021-107751

De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

Audrey Schalk, Margot A. Cousin, Nikita R. Dsouza, Thomas D. Challman, Karen E. Wain, Zoe Powis, Kelly Minks, Aurélien Trimouille, Eulalie Lasseaux, Didier Lacombe, Chloé Angelini, Vincent Michaud, Julien Van-Gils, Nino Spataro, Anna Ruiz, Elizabeth Gabau, Elliot Stolerman, Camerun Washington, Ray Louie, Brendan C. LanpherJennifer L. Kemppainen, Micheil Innes, Frank Kooy, Marije Meuwissen, Alice Goldenberg, Francois Lecoquierre, Gabriella Vera, Karin E.M. Diderich, Beth Sheidley, Christelle Moufawad El Achkar, Meredith Park, Fadi F. Hamdan, Jacques L. Michaud, Ann J. Lewis, Christiane Zweier, André Reis, Matias Wagner, Heike Weigand, Hubert Journel, Boris Keren, Sandrine Passemard, Cyril Mignot, Koen Van Gassen, Eva H. Brilstra, Gina Itzikowitz, Emily O'Heir, Jake Allen, Kirsten A. Donald, Bruce Richard Korf, Tammi Skelton, Michelle Thompson, Nathaniel H. Robin, Natasha L. Rudy, William B. Dobyns, Kimberly Foss, Yuri Alexander Zarate, Katherine A. Bosanko, Yves Alembik, Benjamin Durand, Frederic Tran Mau-Them, Emmanuelle Ranza, Xavier Blanc, Stylianos E. Antonarakis, Kirsty McWalter, Erin Torti, Francisca Millan, Amy Dameron, Mari Tokita, Michael T. Zimmermann, Eric W Klee, Amelie Piton, Benedicte Gerard

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.

Original language	English (US)
Pages (from-to)	965-975
Number of pages	11
Journal	Journal of medical genetics
Volume	59
Issue number	10
DOIs	https://doi.org/10.1136/jmedgenet-2021-107751
State	Published - 2022

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U01MH119689. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank the CREGEMES for its financial support.

Publisher Copyright:
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

genetics
medical
microRNA
missense
mutation
nervous system diseases
Humans
Argonaute Proteins/genetics
Intellectual Disability/genetics
Heterozygote
Amino Acids/genetics
RNA, Messenger
Neurodevelopmental Disorders/genetics

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

Publisher link

10.1136/jmedgenet-2021-107751

Find It

Find It at U of M Libraries

Cite this

Schalk, A., Cousin, M. A., Dsouza, N. R., Challman, T. D., Wain, K. E., Powis, Z., Minks, K., Trimouille, A., Lasseaux, E., Lacombe, D., Angelini, C., Michaud, V., Van-Gils, J., Spataro, N., Ruiz, A., Gabau, E., Stolerman, E., Washington, C., Louie, R., ... Gerard, B. (2022). De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability. Journal of medical genetics, 59(10), 965-975. https://doi.org/10.1136/jmedgenet-2021-107751

Schalk, A, Cousin, MA, Dsouza, NR, Challman, TD, Wain, KE, Powis, Z, Minks, K, Trimouille, A, Lasseaux, E, Lacombe, D, Angelini, C, Michaud, V, Van-Gils, J, Spataro, N, Ruiz, A, Gabau, E, Stolerman, E, Washington, C, Louie, R, Lanpher, BC, Kemppainen, JL, Innes, M, Kooy, F, Meuwissen, M, Goldenberg, A, Lecoquierre, F, Vera, G, Diderich, KEM, Sheidley, B, El Achkar, CM, Park, M, Hamdan, FF, Michaud, JL, Lewis, AJ, Zweier, C, Reis, A, Wagner, M, Weigand, H, Journel, H, Keren, B, Passemard, S, Mignot, C, Van Gassen, K, Brilstra, EH, Itzikowitz, G, O'Heir, E, Allen, J, Donald, KA, Korf, BR, Skelton, T, Thompson, M, Robin, NH, Rudy, NL, Dobyns, WB, Foss, K, Zarate, YA, Bosanko, KA, Alembik, Y, Durand, B, Tran Mau-Them, F, Ranza, E, Blanc, X, Antonarakis, SE, McWalter, K, Torti, E, Millan, F, Dameron, A, Tokita, M, Zimmermann, MT, Klee, EW, Piton, A & Gerard, B 2022, 'De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability', Journal of medical genetics, vol. 59, no. 10, pp. 965-975. https://doi.org/10.1136/jmedgenet-2021-107751

@article{23506cf5a74c454c8f734a34370daf47,

title = "De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability",

abstract = "Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.",

keywords = "genetics, medical, microRNA, missense, mutation, nervous system diseases, Humans, Argonaute Proteins/genetics, Intellectual Disability/genetics, Heterozygote, Amino Acids/genetics, RNA, Messenger, Neurodevelopmental Disorders/genetics",

author = "Audrey Schalk and Cousin, {Margot A.} and Dsouza, {Nikita R.} and Challman, {Thomas D.} and Wain, {Karen E.} and Zoe Powis and Kelly Minks and Aur{\'e}lien Trimouille and Eulalie Lasseaux and Didier Lacombe and Chlo{\'e} Angelini and Vincent Michaud and Julien Van-Gils and Nino Spataro and Anna Ruiz and Elizabeth Gabau and Elliot Stolerman and Camerun Washington and Ray Louie and Lanpher, {Brendan C.} and Kemppainen, {Jennifer L.} and Micheil Innes and Frank Kooy and Marije Meuwissen and Alice Goldenberg and Francois Lecoquierre and Gabriella Vera and Diderich, {Karin E.M.} and Beth Sheidley and {El Achkar}, {Christelle Moufawad} and Meredith Park and Hamdan, {Fadi F.} and Michaud, {Jacques L.} and Lewis, {Ann J.} and Christiane Zweier and Andr{\'e} Reis and Matias Wagner and Heike Weigand and Hubert Journel and Boris Keren and Sandrine Passemard and Cyril Mignot and {Van Gassen}, Koen and Brilstra, {Eva H.} and Gina Itzikowitz and Emily O'Heir and Jake Allen and Donald, {Kirsten A.} and Korf, {Bruce Richard} and Tammi Skelton and Michelle Thompson and Robin, {Nathaniel H.} and Rudy, {Natasha L.} and Dobyns, {William B.} and Kimberly Foss and Zarate, {Yuri Alexander} and Bosanko, {Katherine A.} and Yves Alembik and Benjamin Durand and {Tran Mau-Them}, Frederic and Emmanuelle Ranza and Xavier Blanc and Antonarakis, {Stylianos E.} and Kirsty McWalter and Erin Torti and Francisca Millan and Amy Dameron and Mari Tokita and Zimmermann, {Michael T.} and Klee, {Eric W} and Amelie Piton and Benedicte Gerard",

note = "Funding Information: Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U01MH119689. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank the CREGEMES for its financial support. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

doi = "10.1136/jmedgenet-2021-107751",

language = "English (US)",

volume = "59",

pages = "965--975",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "10",

}

TY - JOUR

T1 - De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

AU - Schalk, Audrey

AU - Cousin, Margot A.

AU - Dsouza, Nikita R.

AU - Challman, Thomas D.

AU - Wain, Karen E.

AU - Powis, Zoe

AU - Minks, Kelly

AU - Trimouille, Aurélien

AU - Lasseaux, Eulalie

AU - Lacombe, Didier

AU - Angelini, Chloé

AU - Michaud, Vincent

AU - Van-Gils, Julien

AU - Spataro, Nino

AU - Ruiz, Anna

AU - Gabau, Elizabeth

AU - Stolerman, Elliot

AU - Washington, Camerun

AU - Louie, Ray

AU - Lanpher, Brendan C.

AU - Kemppainen, Jennifer L.

AU - Innes, Micheil

AU - Kooy, Frank

AU - Meuwissen, Marije

AU - Goldenberg, Alice

AU - Lecoquierre, Francois

AU - Vera, Gabriella

AU - Diderich, Karin E.M.

AU - Sheidley, Beth

AU - El Achkar, Christelle Moufawad

AU - Park, Meredith

AU - Hamdan, Fadi F.

AU - Michaud, Jacques L.

AU - Lewis, Ann J.

AU - Zweier, Christiane

AU - Reis, André

AU - Wagner, Matias

AU - Weigand, Heike

AU - Journel, Hubert

AU - Keren, Boris

AU - Passemard, Sandrine

AU - Mignot, Cyril

AU - Van Gassen, Koen

AU - Brilstra, Eva H.

AU - Itzikowitz, Gina

AU - O'Heir, Emily

AU - Allen, Jake

AU - Donald, Kirsten A.

AU - Korf, Bruce Richard

AU - Skelton, Tammi

AU - Thompson, Michelle

AU - Robin, Nathaniel H.

AU - Rudy, Natasha L.

AU - Dobyns, William B.

AU - Foss, Kimberly

AU - Zarate, Yuri Alexander

AU - Bosanko, Katherine A.

AU - Alembik, Yves

AU - Durand, Benjamin

AU - Tran Mau-Them, Frederic

AU - Ranza, Emmanuelle

AU - Blanc, Xavier

AU - Antonarakis, Stylianos E.

AU - McWalter, Kirsty

AU - Torti, Erin

AU - Millan, Francisca

AU - Dameron, Amy

AU - Tokita, Mari

AU - Zimmermann, Michael T.

AU - Klee, Eric W

AU - Piton, Amelie

AU - Gerard, Benedicte

N1 - Funding Information: Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U01MH119689. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank the CREGEMES for its financial support. Publisher Copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2022

Y1 - 2022

N2 - Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.

AB - Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.

KW - genetics

KW - medical

KW - microRNA

KW - missense

KW - mutation

KW - nervous system diseases

KW - Humans

KW - Argonaute Proteins/genetics

KW - Intellectual Disability/genetics

KW - Heterozygote

KW - Amino Acids/genetics

KW - RNA, Messenger

KW - Neurodevelopmental Disorders/genetics

UR - http://www.scopus.com/inward/record.url?scp=85134474339&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85134474339&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2021-107751

DO - 10.1136/jmedgenet-2021-107751

M3 - Article

C2 - 34930816

AN - SCOPUS:85134474339

SN - 0022-2593

VL - 59

SP - 965

EP - 975

JO - Journal of medical genetics

JF - Journal of medical genetics

IS - 10

ER -

De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

Publisher link

Find It

Other files and links

Fingerprint

Cite this