AGO1 – Neurodevelopmental Disorder with Language Delay and Behavioral Abnormalities, With or Without Seizures

Multiple unrelated patients with de novo AGO1 variants present with a consistent neurodevelopmental phenotype characterized by language delay, behavioral abnormalities and variable seizures, supporting a gene–disease link. To date, four unrelated probands harboring heterozygous in-frame deletions in AGO1 have been reported, including the fourth case with p.Glu376del identified by whole genome sequencing (PMID:39908527). Based on these data and concordant experimental models, the clinical validity for AGO1 in this disorder is classified as Moderate.

Genetic evidence supports an autosomal dominant inheritance pattern with de novo occurrence in all patients. No familial segregation beyond the probands has been observed. The key variant p.Glu376del occurs in the MID–PIWI linker domain and is absent from population databases, indicating a non-recurrent, high-impact lesion in four sporadic cases (PMID:39908527).

Functional studies in multiple organisms demonstrate that AGO1 haploinsufficiency disrupts miRNA pathways critical for neural development. In Drosophila, loss of dFMR1 reduces the Dicer-1–Ago1 complex and lowers mature miR-124a, altering dendritic arborization (PMID:19005053). Similarly, C. elegans models of human AGO1 NDD variants show allele-specific defects in miRNA biogenesis, miRISC formation and downstream gene expression, including orthologs of human NDD genes (PMID:37066388).

Mechanistically, these data support a haploinsufficiency model in which in-frame deletions in AGO1 impair miRNA maturation and neuronal gene regulation. The experimental concordance across species strengthens the link between AGO1 dysfunction and the neurodevelopmental phenotype.

No conflicting evidence has been reported to date. Additional large-scale cohorts and extended segregation analyses could further refine penetrance and expressivity estimates. Clinically, molecular confirmation of AGO1 variants enables precision diagnosis, informs prognostic counseling and may guide future therapeutic targeting of miRNA pathways.

Key Take-home: Heterozygous in-frame deletions in AGO1 cause a moderate-evidence autosomal dominant neurodevelopmental disorder with language delay, behavioral anomalies and seizures amenable to genome-first diagnosis.

References

• WMJ : official publication of the State Medical Society of Wisconsin • 2024 • The University of Wisconsin Undiagnosed Disease Program: Unveiling Rare Neurodevelopmental Disorders in Exome-Negative Patients. PMID:39908527
• The Journal of neuroscience : the official journal of the Society for Neuroscience • 2008 • The steady-state level of the nervous-system-specific microRNA-124a is regulated by dFMR1 in Drosophila. PMID:19005053
• bioRxiv : the preprint server for biology • 2023 • Modeling neurodevelopmental disorder-associated hAGO1 mutations in C. elegans Argonaute ALG-1. PMID:37066388

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