Two Japanese Cases Highlighting Structural and Phenotypic Overlap in AGO1- and AGO2-Related Neurodevelopmental Disorders.
TL;DR
Structural assessment using AlphaFold2-based AGO1 models and the AGO2 crystal structure confirmed positional equivalence of the affected residues, supporting the concept of a shared structural vulnerability across Argonaute paralogs and highlighting RNA-regulatory dysfunction as a coherent pathogenic axis.
Abstract
Pathogenic variants in AGO1 and AGO2, core components of the Argonaute family, have emerged as causes of rare neurodevelopmental disorders characterized by intellectual disability, marked language impairment, behavioral abnormalities, and distinctive craniofacial features. Reported variants cluster at the L1-PAZ boundary, a structurally sensitive region essential for guide-RNA engagement. We describe two unrelated Japanese individuals carrying de novo variants in AGO1(NM_012199.5):c.569T>C p.(Leu190Pro) or AGO2(NM_012154.6):c.544_546del p.(Phe182del), affecting structurally corresponding residues within this boundary. Both individuals exhibited global developmental delay, hypotonia, midface hypoplasia, thin upper lip, elongated facial shape, and reduced cerebral white matter volume, aligning with previously reported AGO1- and AGO2-related phenotypes. Structural assessment using AlphaFold2-based AGO1 models and the AGO2 crystal structure confirmed positional equivalence of the affected residues, supporting the concept of a shared structural vulnerability across Argonaute paralogs. These observations expand the phenotypic spectrum of Argonaute-related neurodevelopmental disorders in the Japanese population and highlight RNA-regulatory dysfunction as a coherent pathogenic axis. Recognition of this clinical gestalt may assist clinicians in prioritizing AGO1 and AGO2 during genomic evaluation of unexplained neurodevelopmental disorders.