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

Schalk A, Cousin MA, Challman TD, Wain KE, Powis Z, Minks K, Trimouille A, Lasseaux E, Lacombre D, Angelini C, Michaud V, Van-Gils J, Spataro N, Ruiz A, Gabau E, Stolerman E, Washington C, Louie RJ, Lanpher BC, Kemppainen JL, Innes AM, Kooy RF, Meuwissen M, Goldenberg A, Lecoquierre F, Vera G, Diderich KEM, Sheidley BR, 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 KL, Brilstra EH, Itzikowitz G, O'Heir E, Allen J, Donald KA, Korf BR, Skelton T, Thompson ML, Robin NH, Rudy N, Dobyns WB, Foss K, Zarate YA, Bosanko KA, Alembik Y, Durand B, Mau-Them FT, Ranza E, Blanc X, Antonarakis SE, Mcwalter K, Torti E, Millan F, Dameron A, Tokita MJ, Zimmermann MT, Klee EW, Piton A, Gerard B (2021)

Publication Type: Journal article

Publication year: 2021


DOI: 10.1136/jmedgenet-2021-107751


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.

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Involved external institutions

Hôpitaux universitaires de Strasbourg (HUS) / University Hospital Strasbourg FR France (FR) Mayo Clinic US United States (USA) (US) Medical College of Wisconsin (MCW) US United States (USA) (US) Geisinger Lewistown Hospital US United States (USA) (US) Ambry Genetics US United States (USA) (US) Centre Hospitalier Universitaire de Bordeaux / CHU Bordeaux FR France (FR) Hospital Parc Tauli ES Spain (ES) Greenwood Genetic Center US United States (USA) (US) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière FR France (FR) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Red Cross War Memorial Children’s Hospital ZA South Africa (ZA) Eli and Edythe L. Broad Institute of MIT and Harvard US United States (USA) (US) University of Arkansas US United States (USA) (US) GeneDX US United States (USA) (US) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) FR France (FR) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona ES Spain (ES) University of Calgary CA Canada (CA) University of Alabama at Birmingham (UAB) US United States (USA) (US) Antwerp University Hospital (UZA) BE Belgium (BE) Université de Caen Basse-Normandie FR France (FR) Erasmus University Medical Center (MC) NL Netherlands (NL) Boston Children's Hospital US United States (USA) (US) CHU Sainte-Justine Research Center CA Canada (CA) Kaiser Permanente Santa Clara Medical Center US United States (USA) (US) Technische Universität München (TUM) DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Hôpital Universitaire Robert-Debré FR France (FR) Swiss Institute Of Genomic Medicine (medigenome) CH Switzerland (CH) Hospital Chubert FR France (FR) University of Washington US United States (USA) (US)

How to cite


Schalk, A., Cousin, M.A., Challman, T.D., Wain, K.E., Powis, Z., Minks, K.,... Gerard, B. (2021). De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability. Journal of Medical Genetics.


Schalk, Audrey, et al. "De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability." Journal of Medical Genetics (2021).

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