TY - JOUR T1 - <em>De novo</em> coding variants in the <em>AGO1</em> gene cause a neurodevelopmental disorder with intellectual disability JF - Journal of Medical Genetics JO - J Med Genet SP - 965 LP - 975 DO - 10.1136/jmedgenet-2021-107751 VL - 59 IS - 10 AU - Audrey Schalk AU - Margot A Cousin AU - Nikita R Dsouza AU - Thomas D Challman AU - Karen E Wain AU - Zoe Powis AU - Kelly Minks AU - Aurélien Trimouille AU - Eulalie Lasseaux AU - Didier Lacombe AU - Chloé Angelini AU - Vincent Michaud AU - Julien Van-Gils AU - Nino Spataro AU - Anna Ruiz AU - Elizabeth Gabau AU - Elliot Stolerman AU - Camerun Washington AU - Ray Louie AU - Brendan C Lanpher AU - Jennifer L Kemppainen AU - Micheil Innes AU - Frank Kooy AU - Marije Meuwissen AU - Alice Goldenberg AU - Francois Lecoquierre AU - Gabriella Vera AU - Karin E M Diderich AU - Beth Sheidley AU - Christelle Moufawad El Achkar AU - Meredith Park AU - Fadi F Hamdan AU - Jacques L Michaud AU - Ann J Lewis AU - Christiane Zweier AU - André Reis AU - Matias Wagner AU - Heike Weigand AU - Hubert Journel AU - Boris Keren AU - Sandrine Passemard AU - Cyril Mignot AU - Koen van Gassen AU - Eva H Brilstra AU - Gina Itzikowitz AU - Emily O'Heir AU - Jake Allen AU - Kirsten A Donald AU - Bruce Richard Korf AU - Tammi Skelton AU - Michelle Thompson AU - Nathaniel H Robin AU - Natasha L Rudy AU - William B Dobyns AU - Kimberly Foss AU - Yuri Alexander Zarate AU - Katherine A Bosanko AU - Yves Alembik AU - Benjamin Durand AU - Frederic Tran Mau-them AU - Emmanuelle Ranza AU - Xavier Blanc AU - Stylianos E Antonarakis AU - Kirsty McWalter AU - Erin Torti AU - Francisca Millan AU - Amy Dameron AU - Mari Tokita AU - Michael T Zimmermann AU - Eric W Klee AU - Amelie Piton AU - Benedicte Gerard Y1 - 2022/10/01 UR - http://jmg.bmj.com/content/59/10/965.abstract 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.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.Data are available in a public, open access repository. Data are available on reasonable request. The variants have been submitted to Clinvar. All other data are available on request. ER -