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.
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AP and BG are joint senior authors.
AS and MAC contributed equally.
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 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.
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