Two Japanese Cases Highlighting Structural and Phenotypic Overlap in AGO1- and AGO2-Related Neurodevelopmental...

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Pathogenic variants in Argonaute (AGO) genes AGO1 and AGO2 are linked to rare neurodevelopmental disorders.
• These disorders manifest with intellectual disability, language impairment, behavioral issues, and craniofacial anomalies.
• Known variants often affect the L1-PAZ boundary, crucial for guide-RNA binding.

Purpose of the Study:

• To report novel de novo variants in AGO1 and AGO2 in two unrelated Japanese individuals.
• To characterize the clinical and structural implications of these variants.
• To expand the understanding of Argonaute-related neurodevelopmental disorders.

Main Methods:

• Clinical phenotyping of two Japanese individuals with de novo variants in AGO1 and AGO2.
• Genetic variant analysis (NM_012199.5:c.569T>C in AGO1, NM_012154.6:c.544_546del in AGO2).
• Structural modeling using AlphaFold2 and existing AGO2 crystal structure to assess residue positional equivalence.

Main Results:

• Both individuals presented with global developmental delay, hypotonia, midface hypoplasia, thin upper lip, elongated face, and reduced white matter volume.
• The identified variants p.(Leu190Pro) in AGO1 and p.(Phe182del) in AGO2 affect structurally equivalent residues at the L1-PAZ boundary.
• Structural analysis confirmed shared vulnerability across AGO paralogs at this critical region.

Conclusions:

• The findings expand the phenotypic spectrum of AGO1- and AGO2-related neurodevelopmental disorders in the Japanese population.
• RNA-regulatory dysfunction is confirmed as a key pathogenic mechanism.
• Clinical recognition of this phenotype can aid in prioritizing AGO1 and AGO2 in genomic evaluations for unexplained neurodevelopmental disorders.