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 journalArticlepeer-review


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. Conclusion: Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

Original languageEnglish (US)
Article numberjmedgenet-2021-107751
JournalJournal of medical genetics
StateAccepted/In press - 2022


  • genetics
  • medical
  • microRNA
  • missense
  • mutation
  • nervous system diseases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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