Intellectual disability (ID) and autism spectrum disorders (ASDs) are the most common developmental disorders in humans. Combined, they affect between 3% and 5% of the population. Although high-throughput genomic methods are rapidly increasing the pool of ASD genes, many cases remain idiopathic. AGO1 is one of the less-known genes related to ID/ASD. This gene encodes a core member protein of the RNA-induced silencing complex, which suppresses mRNA expression through cleavage, degradation, and/or translational repression. Generally, patients with defects in the AGO1 gene manifest varying degrees of ID, speech delay, and autistic behaviors. Herein, we used whole-exome sequencing (WES) to investigate an Iranian family with two affected members one of whom manifested ID and autism and the other showed borderline ID and schizophrenia. WES analysis identified a novel heterozygous truncating variant (NM_012199.5:c.1298G > A, p.Trp433Ter) in the AGO1 gene that co-segregated with the phenotypes using Sanger sequencing. Moreover, the structural analysis showed that due to this variant, two critical domains (Mid and PIWI) of the AGO1 protein have been lost, which has a detrimental effect on the protein's function and structure. To the best of our knowledge, schizophrenia has not been reported in patients with AGO1 deficiency, which is a novel phenotypic finding that expands the AGO1-related behavioral disorders. Moreover, this study's findings determined that patients with the same variant in the AGO1 gene may show heterogeneity in manifested phenotypes.
Keywords: AGO1; RICS complex; autism spectrum disorders; EIF2C1; intellectual disability; schizophrenia.
© 2023 John Wiley & Sons Ltd/University College London.