RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP 965
OP 975
DO 10.1136/jmedgenet-2021-107751
VO 59
IS 10
A1 Audrey Schalk
A1 Margot A Cousin
A1 Nikita R Dsouza
A1 Thomas D Challman
A1 Karen E Wain
A1 Zoe Powis
A1 Kelly Minks
A1 Aurélien Trimouille
A1 Eulalie Lasseaux
A1 Didier Lacombe
A1 Chloé Angelini
A1 Vincent Michaud
A1 Julien Van-Gils
A1 Nino Spataro
A1 Anna Ruiz
A1 Elizabeth Gabau
A1 Elliot Stolerman
A1 Camerun Washington
A1 Ray Louie
A1 Brendan C Lanpher
A1 Jennifer L Kemppainen
A1 Micheil Innes
A1 Frank Kooy
A1 Marije Meuwissen
A1 Alice Goldenberg
A1 Francois Lecoquierre
A1 Gabriella Vera
A1 Karin E M Diderich
A1 Beth Sheidley
A1 Christelle Moufawad El Achkar
A1 Meredith Park
A1 Fadi F Hamdan
A1 Jacques L Michaud
A1 Ann J Lewis
A1 Christiane Zweier
A1 André Reis
A1 Matias Wagner
A1 Heike Weigand
A1 Hubert Journel
A1 Boris Keren
A1 Sandrine Passemard
A1 Cyril Mignot
A1 Koen van Gassen
A1 Eva H Brilstra
A1 Gina Itzikowitz
A1 Emily O'Heir
A1 Jake Allen
A1 Kirsten A Donald
A1 Bruce Richard Korf
A1 Tammi Skelton
A1 Michelle Thompson
A1 Nathaniel H Robin
A1 Natasha L Rudy
A1 William B Dobyns
A1 Kimberly Foss
A1 Yuri Alexander Zarate
A1 Katherine A Bosanko
A1 Yves Alembik
A1 Benjamin Durand
A1 Frederic Tran Mau-them
A1 Emmanuelle Ranza
A1 Xavier Blanc
A1 Stylianos E Antonarakis
A1 Kirsty McWalter
A1 Erin Torti
A1 Francisca Millan
A1 Amy Dameron
A1 Mari Tokita
A1 Michael T Zimmermann
A1 Eric W Klee
A1 Amelie Piton
A1 Benedicte Gerard
YR 2022
UL http://jmg.bmj.com/content/59/10/965.abstract
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.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.