Genetic Causes and Modifiers of Autism Spectrum Disorder

Rylaarsdam, Lauren; Guemez‐Gamboa, Alicia

doi:10.3389/fncel.2019.00385

Cited by 369 publications

(287 citation statements)

References 219 publications

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“…Because autism mutations are predominantly de novo and can occur in genes that function in a variety of tissues during development (4,16,21,31), it can also be difficult to define the relevant developmental and cellular contexts in which to study ASD mechanisms. Finally, many ASD mutations increase susceptibility but do not consistently cause autism phenotypes in humans or in animal models (32,33).…”

Section: Resultsmentioning

confidence: 99%

Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism

Wenderski

Wang

Krokhotin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such “early activation” genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

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Section: Resultsmentioning

confidence: 99%

Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism

Wenderski

Wang

Krokhotin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…It is estimated that up to 1000 genes are potentially implicated ASD 21,22 , making it one of the most complex disorders. Genetic factors are known to play an important role in ASD aetiology, but that their elucidation is a work in progress [23][24][25] .…”

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confidence: 99%

Genetic landscape of autism spectrum disorder in Vietnamese children

Tran

Bui

et al. 2020

Sci Rep

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Autism spectrum disorder (ASD) is a complex disorder with an unclear aetiology and an estimated global prevalence of 1%. However, studies of ASD in the Vietnamese population are limited. Here, we first conducted whole exome sequencing (WES) of 100 children with ASD and their unaffected parents. Our stringent analysis pipeline was able to detect 18 unique variants (8 de novo and 10 ×-linked, all validated), including 12 newly discovered variants. Interestingly, a notable number of X-linked variants were detected (56%), and all of them were found in affected males but not in affected females. We uncovered 17 genes from our ASD cohort in which CHD8, DYRK1A, GRIN2B, SCN2A, OFD1 and MDB5 have been previously identified as ASD risk genes, suggesting the universal aetiology of ASD for these genes. In addition, we identified six genes that have not been previously reported in any autism database: CHM, ENPP1, IGF1, LAS1L, SYP and TBX22. Gene ontology and phenotype-genotype analysis suggested that variants in IGF1, SYP and LAS1L could plausibly confer risk for ASD. Taken together, this study adds to the genetic heterogeneity of ASD and is the first report elucidating the genetic landscape of ASD in Vietnamese children.Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that includes autism, Asperger's syndrome and pervasive developmental disorder not otherwise specified and is characterized by restricted repetitive behaviour, delays in language development and lack of reciprocal social communication and interaction 1 . The common psychiatric and cognitive comorbidities with ASD include intellectual disability (ID) 2-4 , sleep deprivation 5,6 and epilepsy (EP) 3,7 .Recent studies have gradually emphasized the role of genetics in ASD, with up to 25% of ASD cases having genetically identifiable causes 8 . Males have a 4-fold higher incidence of ASD than females 9 , suggesting the involvement of genetics in the aetiology of ASD. Previous studies have shown that 5% to 15% of patients with ASD have inherited copy number variations (CNVs) or de novo CNVs in some affected genes with synaptic function 10 . Genome-wide association studies have indicated that common variations are risk factors for ASD 11,12 . Meanwhile, de novo CNV and loss of function (LoF) mutations merely explain 2.6% of the variance in liability 12 . Other studies have revealed that non-coding de novo mutations in the promoter regions also affect ASD 13,14 . Recent genomic studies with large samples have explored new genes linked to ASD 15,16 . To date, over 100 genes have been identified as strongly linked to the risk of ASD 17,18 and enriched in the following three main pathways: chromatin remodelling, transcription and splicing, and synaptic function [18][19][20] . In fact, ASD is highly genetically heterogeneous due to multiple familial inheritance patterns and the occurrence of a large number of de novo variations. It is estimated that up to 1000 genes are potentially implicated ASD 21,22 , making it one of the most complex disorders. G...

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“…WGS analysis offers a more comprehensive view of the genome than genotyping array by giving access to almost all of the genetic variants that are present in an individual (coding and non-coding regions). Thus, the exploration of the individual genetic variation is not restricted to single nucleotide variants (SNVs), as it allows the identification of structural variants (SVs) as well [2,19,107,108]. Moreover, continuous improvements in knowledge of the transcriptome, known interactions within and between different biological entities, related ontologies, and bioinformatics tools are providing a better understanding and more precise annotation of the variant effects.…”

Section: Wgs Approach For Modifier Studiesmentioning

confidence: 99%

Genetic Modifiers and Rare Mendelian Disease

Rahit

Tarailo‐Graovac

2020

Genes

113

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Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap.

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Genetic Causes and Modifiers of Autism Spectrum Disorder

Cited by 369 publications

References 219 publications

Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism

Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism

Genetic landscape of autism spectrum disorder in Vietnamese children

Genetic Modifiers and Rare Mendelian Disease

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