De novo variants in <scp><i>AGO1</i></scp> recapitulate a heterogeneous neurodevelopmental disorder phenotype

Niu, Yue; Qian, Qiaoqiao; Li, Juan; Gong, Pan; Jiao, Xianru; Xiao, Bo; Long, Lili; Yang, Zhixian

doi:10.1111/cge.14114

Cited by 5 publications

(8 citation statements)

References 17 publications

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“…Kleefstra Syndrome is the result of mutations in the H3K9me3 writer EHMT1 34 and Rett Syndrome is caused by mutations in the MECP2 gene that codes for a DNA-methylase that modifies the DNA where it contacts H3K9 residues 35–37 . Autism-like syndromes have also been reported in cases of de novo deletions of AGO1 38,39 . We, and others, have identified the H3K9me3 demethylases KDM4B and KDM4C as risk-genes for ASD (Table S11) 9 .…”

Section: Discussionmentioning

confidence: 97%

Maintenance of Heterochromatin links Chromatin Modifiers and Neurodevelopment in Autism Spectrum Disorder

Garvin,

Kainer

2023

Preprint

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Autism spectrum disorder (ASD) is a highly heritable and highly heterogeneous neuropsychiatric condition whose cause is still unknown because there are no recurrent genes found among diagnosed individuals. One of the most common functional properties of the many reported risk-genes for autism is “chromatin modification” but it is not known how this biological process relates to neurodevelopment and autism. We recently reported frequent, recurrent genomic structural variants (SVs) in two cohorts of individuals with autism that were identified using non-Mendelian inheritance (NMI) patterns in family trios. The genes harboring the SVs participate in neurodevelopment, glutamate signaling, and chromatin modification, confirming previous reports and providing greater detail for these processes in ASD. The majority of these ASD-associated SVs (ASD-SV) were found in non-coding regions of the genome and were enriched for expression quantitative trait loci (eQTL) suggesting that gene dysregulation results from these genomic disruptions rather than alteration of proteins. Here, we intersect the ASD-SV from our earlier work with different gene regulatory and epigenetic multiomic layers to understand how they may function to produce autism. Our results indicate that the core of ASD resides in the dysregulation of a process called RNA-induced Initiation of Transcriptional gene Silencing (RITS) that is meant to maintain heterochromatin and produces SVs in the genes within these chromosomal regions, resulting in alterations in brain development. This finally links reported ASD-risk genes involved in chromatin remodeling with neurodevelopment. In addition, it may explain the role ofde novomutations in ASD and provide a framework for more accurate diagnostics and endophenotypes.

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Section: Discussionmentioning

confidence: 97%

Maintenance of Heterochromatin links Chromatin Modifiers and Neurodevelopment in Autism Spectrum Disorder

Garvin,

Kainer

2023

Preprint

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“…Although most patients could make a sentence, a few patients never acquired language (Schalk et al., 2022). Moreover, other comorbidities, including seizure, motor developmental delay, hypotonia, and behavioral features, including autistic features, self‐harm behavior, attention deficit, hyperactivity, and anxiety, have also been reported (Niu et al., 2022; Schalk et al., 2022). The manifested seizures are heterogeneous; some show focal and some express febrile seizure (Niu et al., 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, other comorbidities, including seizure, motor developmental delay, hypotonia, and behavioral features, including autistic features, self‐harm behavior, attention deficit, hyperactivity, and anxiety, have also been reported (Niu et al., 2022; Schalk et al., 2022). The manifested seizures are heterogeneous; some show focal and some express febrile seizure (Niu et al., 2022). Seizures remain drug‐resistant in some patients, but seizures were controlled in others by prescribing a combination of antiepileptic drugs such as levetiracetam, lacosamide, perampanel, clonazepam, valproate, lamotrigine, and oxcarbazepine.…”

Section: Discussionmentioning

confidence: 99%

A novel heterozygous truncating variant in the AGO1 gene in an Iranian family with schizophrenia as an unreported symptom

Mir,

Khorram,

Song

et al. 2023

Annals of Human Genetics

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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.

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“…The pLi score of AGO1 , provided in the gnomAD database, is 1, suggesting that haploinsufficiency is likely to be the main disease driver. De novo missense variants have been reported in AGO1 in individuals with a broad spectrum of NDDs, including global DD, ID, autism spectrum disorder (ASD), hypotonia, dysmorphism, behavioral features, and language impairment with or without epilepsy [ 49 , 50 , 51 , 52 ]. The reported variants of AGO1 gene are mainly nucleotide changes, while in our patient, a deletion including the first eight exons of the transcript was revealed.…”

Section: Discussionmentioning

confidence: 99%

Dyslexia and Attention Deficit Hyperactivity Disorder Associated to a De Novo 1p34.3 Microdeletion

Galesi

Blasi

Grillo

et al. 2022

Genes

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The authors report on a boy with dyslexia and attention deficit hyperactivity disorder. A protocol of standardized tests assessed the neuroadaptive profile, allowing deep neuropsychiatric phenotyping. In addition to the diagnosis of dyslexia and attention deficit hyperactivity disorder, such methodology led to endeavor cognitive, adaptive, and academic skills. Chromosomal microarray analysis detected a 452.4 Kb de novo heterozygous microdeletion in chromosomal region 1p34.3, including seven OMIM genes. The authors took a thorough evaluation of the association to the phenotype of the deleted genes. Further reports could strengthen such association.

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De novo variants in AGO1 recapitulate a heterogeneous neurodevelopmental disorder phenotype

Cited by 5 publications

References 17 publications

Maintenance of Heterochromatin links Chromatin Modifiers and Neurodevelopment in Autism Spectrum Disorder

Maintenance of Heterochromatin links Chromatin Modifiers and Neurodevelopment in Autism Spectrum Disorder

A novel heterozygous truncating variant in the AGO1 gene in an Iranian family with schizophrenia as an unreported symptom

Dyslexia and Attention Deficit Hyperactivity Disorder Associated to a De Novo 1p34.3 Microdeletion

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