AGO3 and Neurodevelopmental Disorder

This summary reviews the association between AGO3 (HGNC:18421) and neurodevelopmental disorder (MONDO_0700092). A de novo nonsense variant in AGO3, c.1324C>T (p.Gln442Ter), was identified in a 6‑year‑old female patient presenting with global developmental delay (PMID:38995884). The comprehensive trio‑WGS analysis in this case report provided the initial evidence for AGO3 involvement in neurodevelopmental pathology.

Integrating additional data from a burden re‑analysis of neurodevelopmental disorder cohorts, AGO3 emerged as one of seven candidate genes harboring qualifying de novo variants (PMID:38965372). Although the number of probands is modest, the recurrence of de novo mutations in independent studies strengthens the potential causative link between AGO3 and neurodevelopmental deficits. The observed clinical features include global developmental delay, with additional reports of intellectual disability and autism spectrum features further broadening the phenotypic spectrum.

The genetic evidence is supported by a clear variant spectrum: the reported nonsense variant c.1324C>T (p.Gln442Ter) is highly disruptive, leading to a truncated protein. Despite the absence of multi‑family segregation data, the de novo origin of this variant in a sporadic case, along with its absence in population databases, provides relevant support for pathogenicity. The inclusion of AGO3 in burden analyses across multiple patients indicates an enrichment of rare, deleterious variants in individuals with neurodevelopmental disorders.

Functional studies offer additional corroboration. In an independent investigation focusing on miRNA‑mediated regulation, AGO3 was implicated in the formation of a non‑canonical miRISC complex that mediates selective degradation of target mRNAs (PMID:33215742). These experiments demonstrate that altered AGO3 function can contribute to pathological outcomes, a mechanism that may extend to neurodevelopmental processes.

Together, the clinical, genetic, and functional findings coalesce into a coherent narrative that supports AGO3 as a candidate gene in neurodevelopmental disorder pathogenesis. Although the evidence is emerging, the integration of de novo variant data in a case report with larger burden re‑analysis and supportive functional assays meets the criteria for a moderate gene‑disease association.

Key take‑home: The combined clinical and experimental evidence, despite currently limited numbers, positions AGO3 as a promising candidate gene for neurodevelopmental disorder, underscoring its potential utility in diagnostic decision‑making, commercial applications, and future research endeavors.

References

• The American journal of case reports • 2024 • Novel de Novo Nonsense Variants in AGO3 and KHSRP: Insights into Global Developmental Delay and Autism Spectrum Disorders through Whole Genome Analysis PMID:38995884
• European journal of human genetics : EJHG • 2024 • Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes PMID:38965372
• The EMBO journal • 2020 • An alternative miRISC targets a cancer‑associated coding sequence mutation in FOXL2 PMID:33215742

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