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.
- nervous system diseases
Data availability statement
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.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
AP and BG are joint senior authors.
AS and MAC contributed equally.
Correction notice This article has been correcred since it published Online First. Funding information have been added to the article.
Contributors AS, MAC, AP and BG compiled the molecular and clinical data; TDC, KEW, ZP, KM, AT, EL, DL, CA, VM, JV-G, NS, AR, EG, ES, CW, RJL, BCL, JLK, MI, FK, MM, AG, FL, GV, KEMD, BRS, CMEA, MP, FFH, JLM, AJL, CZ, AR, MW, HW, HJ, BK, SP, CM, KLIVG, EHB, GI, EOH, JA, KAD, BRK, TS, NHR, NR, WBD, KF, YAZ, KAB, YA, BD, FTMT, ER, XB, SEA, KM, ET, FM, AD, MJT, MTZ and NRD contributed to clinical and molecular data and reviewed the manuscript; NRD and MTZ performed the 3D modelling analyses; EWK, AP and BG conceived, coordinated and supervised the study; AS, MAC, AP and BG wrote the manuscript. AP acts as a guarantor.
Funding Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U01MH119689. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank the CREGEMES for its financial support.
Competing interests KMW, ET, FM, AD and MJT are employees of GeneDx. ZP and KM are employees of Ambry Genetics.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.