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Schalk, A.* ; Cousin, M.A.* ; Challman, T.D.* ; Wain, K.E.* ; 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, R.J.* ; Lanpher, B.C.* ; Kemppainen, J.L.* ; Innes, A.M.* ; Kooy, R.F.* ; Meuwissen, M.* ; Goldenberg, A.* ; Lecoquierre, F.* ; Vera, G.* ; Diderich, K.E.M.* ; Sheidley, B.R.* ; El Achkar, C.M.* ; Park, M.* ; Hamdan, F.F.* ; Michaud, J.L.* ; Lewis, A.J.* ; Zweier, C.* ; Reis, A.* ; Wagner, M. ; Weigand, H.* ; Journel, H.* ; Keren, B.* ; Passemard, S.* ; Mignot, C.* ; van Gassen, K.L.* ; Brilstra, E.H.* ; Itzikowitz, G.* ; O'Heir, E.* ; Allen, J.* ; Donald, K.A.* ; Korf, B.R.* ; Skelton, T.* ; Thompson, M.L.* ; Robin, N.H.* ; Rudy, N.* ; Dobyns, W.B.* ; Foss, K.* ; Zarate, Y.A.* ; Bosanko, K.A.* ; Alembik, Y.* ; Durand, B.* ; Mau-them, F.T.* ; Ranza, E.* ; Blanc, X.* ; Antonarakis, S.E.* ; McWalter, K.* ; Torti, E.* ; Millan, F.* ; Dameron, A.* ; Tokita, M.J.* ; Zimmermann, M.T.* ; Klee, E.W.* ; Piton, A.* ; Gérard, B.*

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

J. Med. Genet. 59, 965-975 (2021)
Postprint DOI PMC
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Microrna ; Genetics ; Medical ; Mutation ; Missense ; Nervous System Diseases; Mutations; Database
ISSN (print) / ISBN 0022-2593
e-ISSN 1468-6244
Journal Journal of Medical Genetics
Quellenangaben Volume: 59, Issue: 10, Pages: 965-975 Article Number: , Supplement: ,
Publisher BMJ Publishing Group
Publishing Place British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants CREGEMES