AGO2 – Lessel-Kreienkamp syndrome

Lessel-Kreienkamp syndrome (MONDO:0030897) is an autosomal dominant neurodevelopmental disorder characterized by intellectual disability. In a Chinese family, whole-exome sequencing identified a heterozygous variant in AGO2, c.2149T>C (p.Cys717Arg), which segregated with intellectual disability in all four affected individuals and was absent in unaffected relatives (PMID:40574801). The variant occurs at a conserved residue within the PIWI domain and is classified as likely pathogenic by ACMG guidelines based on segregation and in silico predictive evidence.

AGO2 encodes the core slicer component of the RNA-induced silencing complex (RISC), essential for microRNA-mediated gene regulation in neuronal development. Although no direct functional assays of c.2149T>C (p.Cys717Arg) have been performed, in silico modeling predicts disruption of AGO2 folding. Broad functional studies of germline AGO2 mutations demonstrate impaired RISC assembly, defective mRNA silencing, and neurological phenotypes in patients, supporting a haploinsufficiency mechanism (PMID:33199684). No conflicting reports have been described for AGO2 in Lessel-Kreienkamp syndrome.

Key Take-home: AGO2 should be included in diagnostic panels for autosomal dominant intellectual disability syndromes, and the c.2149T>C (p.Cys717Arg) variant warrants clinical evaluation in similar presentations.

References

• Frontiers in Genetics • 2025 • Identification of a novel AGO2 variant causing LESKRES in a Chinese family with intellectual disability. PMID:40574801
• Nature Communications • 2020 • Germline AGO2 mutations impair RNA interference and human neurological development. PMID:33199684

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