Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Schalk A

PROVIDER: S-EPMC9241146 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Schalk Audrey A Cousin Margot A MA Dsouza Nikita R NR Challman Thomas D TD Wain Karen E KE Powis Zoe Z Minks Kelly K Trimouille Aurélien A Lasseaux Eulalie E Lacombe Didier D Angelini Chloé C Michaud Vincent V Van-Gils Julien J Spataro Nino N Ruiz Anna A Gabau Elizabeth E Stolerman Elliot E Washington Camerun C Louie Ray R Lanpher Brendan C BC Kemppainen Jennifer L JL Innes Micheil M Kooy Frank F Meuwissen Marije M Goldenberg Alice A Lecoquierre Francois F Vera Gabriella G Diderich Karin E M KEM Sheidley Beth B El Achkar Christelle Moufawad CM Park Meredith M Hamdan Fadi F FF Michaud Jacques L JL Lewis Ann J AJ Zweier Christiane C Reis André A Wagner Matias M Weigand Heike H Journel Hubert H Keren Boris B Passemard Sandrine S Mignot Cyril C van Gassen Koen K Brilstra Eva H EH Itzikowitz Gina G O'Heir Emily E Allen Jake J Donald Kirsten A KA Korf Bruce Richard BR Skelton Tammi T Thompson Michelle M Robin Nathaniel H NH Rudy Natasha L NL Dobyns William B WB Foss Kimberly K Zarate Yuri Alexander YA Bosanko Katherine A KA Alembik Yves Y Durand Benjamin B Tran Mau-Them Frederic F Ranza Emmanuelle E Blanc Xavier X Antonarakis Stylianos E SE McWalter Kirsty K Torti Erin E Millan Francisca F Dameron Amy A Tokita Mari M Zimmermann Michael T MT Klee Eric W EW Piton Amelie A Gerard Benedicte B

Journal of medical genetics 20211215 10

<h4>Background</h4>High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).<h4>Methods</h4>This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous <i>AGO1</i> coding variants, occurring de novo for all those whose transmission could have been verified (26/28).<h4>Results</h4>A total of 15 unique variants leading to amino acid changes or deletions were identified: 1 ...[more]

PMID: 34930816

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