scholarly journals Genetic contributions to autism spectrum disorder

2021 ◽  
pp. 1-14
Author(s):  
A. Havdahl ◽  
M. Niarchou ◽  
A. Starnawska ◽  
M. Uddin ◽  
C. van der Merwe ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
De Novo ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Individual Risk ◽  
Future Research ◽  
Risk Genes

Abstract Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.

scholarly journals Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

2021 ◽  
Author(s):  
Ricardo Harripaul ◽  
Ansa Rabia ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Ashlyn Rodrigues ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
De Novo ◽  
Splice Variants ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Loss Of Function ◽  
Candidate Sequence

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that affects about 1 in 55 children worldwide and imposes enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies have investigated ASD genetics in consanguineous populations and point towards AR as an under-appreciated source of ASD variants. Here, we used trio whole exome sequencing (WES) to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. In total, we report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss) and 47% non-synonymous. Our analysis indicates an enrichment of previously identified and candidate AR genes. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID), such as AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335, and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified candidate biallelic exonic loss CNVs a number of trios, implicating genes including DNAH7, and DHRS4/DHRS4L2.

scholarly journals Risk Factors for Unhealthy Weight Gain and Obesity among Children with Autism Spectrum Disorder

2019 ◽  
Vol 20 (13) ◽  
pp. 3285 ◽  
Author(s):  
Khushmol K. Dhaliwal ◽  
Camila E. Orsso ◽  
Caroline Richard ◽  
Andrea M. Haqq ◽  
Lonnie Zwaigenbaum
Keyword(s):  
Risk Factors ◽  
Autism Spectrum Disorder ◽  
Weight Gain ◽  
Autism Spectrum ◽  
Lifestyle Factors ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Future Research ◽  
Children With Asd ◽  
Unhealthy Weight

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by social and communication deficits and repetitive behaviors. Children with ASD are also at a higher risk for developing overweight or obesity than children with typical development (TD). Childhood obesity has been associated with adverse health outcomes, including insulin resistance, diabetes, heart disease, and certain cancers. Importantly some key factors that play a mediating role in these higher rates of obesity include lifestyle factors and biological influences, as well as secondary comorbidities and medications. This review summarizes current knowledge about behavioral and lifestyle factors that could contribute to unhealthy weight gain in children with ASD, as well as the current state of knowledge of emerging risk factors such as the possible influence of sleep problems, the gut microbiome, endocrine influences and maternal metabolic disorders. We also discuss some of the clinical implications of these risk factors and areas for future research.

scholarly journals Sensory and repetitive behaviors among children with autism spectrum disorder at home

Autism ◽  
2016 ◽  
Vol 21 (2) ◽  
pp. 142-154 ◽  
Author(s):  
Anne V Kirby ◽  
Brian A Boyd ◽  
Kathryn L Williams ◽  
Richard A Faldowski ◽  
Grace T Baranek
Keyword(s):  
Autism Spectrum Disorder ◽  
Video Recording ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Free Play ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Future Research ◽  
Sensory Modalities ◽  
Behavior Types

Atypical sensory and repetitive behaviors are defining features of autism spectrum disorder and are thought to be influenced by environmental factors; however, there is a lack of naturalistic research exploring contexts surrounding these behaviors. This study involved video recording observations of 32 children with autism spectrum disorder (2–12 years of age) engaging in sensory and repetitive behaviors during home activities. Behavioral coding was used to determine what activity contexts, sensory modalities, and stimulus characteristics were associated with specific behavior types: hyperresponsive, hyporesponsive, sensory seeking, and repetitive/stereotypic. Results indicated that hyperresponsive behaviors were most associated with activities of daily living and family-initiated stimuli, whereas sensory seeking behaviors were associated with free play activities and child-initiated stimuli. Behaviors associated with multiple sensory modalities simultaneously were common, emphasizing the multi-sensory nature of children’s behaviors in natural contexts. Implications for future research more explicitly considering context are discussed.

scholarly journals An Epigenetically Distinct Subset of Children With Autism Spectrum Disorder Resulting From Differences in Blood Cell Composition

2021 ◽  
Vol 12 ◽  
Author(s):  
Maryam Jangjoo ◽  
Sarah J. Goodman ◽  
Sanaa Choufani ◽  
Brett Trost ◽  
Stephen W. Scherer ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Blood Cell ◽  
Autism Spectrum ◽  
Differential Methylation ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Risk Genes ◽  
Immune Systems ◽  
Cell Composition ◽  
Children With Asd

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that often involves impaired cognition, communication difficulties and restrictive, repetitive behaviors. ASD is extremely heterogeneous both clinically and etiologically, which represents one of the greatest challenges in studying the molecular underpinnings of ASD. While hundreds of ASD-associated genes have been identified that confer varying degrees of risk, no single gene variant accounts for >1% of ASD cases. Notably, a large number of ASD-risk genes function as epigenetic regulators, indicating potential epigenetic dysregulation in ASD. As such, we compared genome-wide DNA methylation (DNAm) in the blood of children with ASD (n = 265) to samples from age- and sex-matched, neurotypical controls (n = 122) using the Illumina Infinium HumanMethylation450 arrays.Results: While DNAm patterns did not distinctly separate ASD cases from controls, our analysis identified an epigenetically unique subset of ASD cases (n = 32); these individuals exhibited significant differential methylation from both controls than the remaining ASD cases. The CpG sites at which this subset was differentially methylated mapped to known ASD risk genes that encode proteins of the nervous and immune systems. Moreover, the observed DNAm differences were attributable to altered blood cell composition, i.e., lower granulocyte proportion and granulocyte-to-lymphocyte ratio in the ASD subset, as compared to the remaining ASD cases and controls. This ASD subset did not differ from the rest of the ASD cases in the frequency or type of high-risk genomic variants.Conclusion: Within our ASD cohort, we identified a subset of individuals that exhibit differential methylation from both controls and the remaining ASD group tightly associated with shifts in immune cell type proportions. This is an important feature that should be assessed in all epigenetic studies of blood cells in ASD. This finding also builds on past reports of changes in the immune systems of children with ASD, supporting the potential role of altered immunological mechanisms in the complex pathophysiology of ASD. The discovery of significant molecular and immunological features in subgroups of individuals with ASD may allow clinicians to better stratify patients, facilitating personalized interventions and improved outcomes.

scholarly journals Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

2017 ◽  
Author(s):  
Deidre R. Krupp ◽  
Rebecca A. Barnard ◽  
Yannis Duffourd ◽  
Sara A. Evans ◽  
Ryan M. Mulqueen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Large Family ◽  
Recurrence Risk ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Sequencing Data ◽  
Full Cohort ◽  
Risk Genes ◽  
Family Based

AbstractGenetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. We systematically evaluated PMMs by leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection. We found evidence that 11% of published single nucleotide variant (SNV) de novo mutations are potentially PMMs. We then developed a robust SNV PMM calling approach that leverages complementary callers, logistic regression modeling, and additional heuristics. Using this approach, we recalled SNVs and found that 22% of de novo mutations likely occur as PMMs in children. Unexpectedly, we found a significant burden of synonymous PMMs in probands that are predicted to alter splicing. We found no evidence of missense PMM burden in the full cohort. However, we did observe increased signal for missense PMMs in families without germline mutations in probands, which strengthens in genes intolerant to mutations. We also determined that 7-11% of parental mosaics are transmitted to children. Parental mosaic mutations make up 6.8% of all mutations newly germline in children, which has important implications for recurrence risk. PMMs intersect previously implicated high confidence and other ASD candidate risk genes, further suggesting that this class of mutations contribute to ASD risk. We also identified PMMs in novel candidate risk genes involved with chromatin remodeling or neurodevelopment. We estimate that PMMs contribute risk to 4-8% of simplex ASD cases. Overall, these findings argue for future studies of PMMs in ASD and related-disorders.

scholarly journals Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands

2021 ◽  
Author(s):  
Kealan Pugsley ◽  
Stephen W. Scherer ◽  
Mark A. Bellgrove ◽  
Ziarih Hawi
Keyword(s):  
Autism Spectrum Disorder ◽  
Oxidative Dna Damage ◽  
De Novo ◽  
Genetic Material ◽  
Environmental Exposures ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Individual Risk ◽  
De Novo Mutations ◽  
Birth Cohorts

AbstractAlthough the full aetiology of autism spectrum disorder (ASD) is unknown, familial and twin studies demonstrate high heritability of 60–90%, indicating a predominant role of genetics in the development of the disorder. The genetic architecture of ASD consists of a complex array of rare and common variants of all classes of genetic variation usually acting additively to augment individual risk. The relative contribution of heredity in ASD persists despite selective pressures against the classic autistic phenotype; a phenomenon thought to be explained, in part, by the incidence of spontaneous (or de novo) mutations. Notably, environmental exposures attributed as salient risk factors for ASD may play a causal role in the emergence of deleterious de novo variations, with several ASD-associated agents having significant mutagenic potential. To explore this hypothesis, this review article assesses published epidemiological data with evidence derived from assays of mutagenicity, both in vivo and in vitro, to determine the likely role such agents may play in augmenting the genetic liability in ASD. Broadly, these exposures were observed to elicit genomic alterations through one or a combination of: (1) direct interaction with genetic material; (2) impaired DNA repair; or (3) oxidative DNA damage. However, the direct contribution of these factors to the ASD phenotype cannot be determined without further analysis. The development of comprehensive prospective birth cohorts in combination with genome sequencing is essential to forming a causal, mechanistic account of de novo mutations in ASD that links exposure, genotypic alterations, and phenotypic consequences.

scholarly journals Genomic selection signatures in autism spectrum disorder identifies cognitive genomic tradeoff and its relevance in paradoxical phenotypes of deficits versus potentialities

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anil Prakash ◽  
Moinak Banerjee
Keyword(s):  
Autism Spectrum Disorder ◽  
Brain Function ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Evolutionary Significance ◽  
Biological Interaction ◽  
Risk Genes ◽  
Brain Functions ◽  
Risk Snps

AbstractAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by paradoxical phenotypes of deficits as well as gain in brain function. To address this a genomic tradeoff hypothesis was tested and followed up with the biological interaction and evolutionary significance of positively selected ASD risk genes. SFARI database was used to retrieve the ASD risk genes while for population datasets 1000 genome data was used. Common risk SNPs were subjected to machine learning as well as independent tests for selection, followed by Bayesian analysis to identify the cumulative effect of selection on risk SNPs. Functional implication of these positively selected risk SNPs was assessed and subjected to ontology analysis, pertaining to their interaction and enrichment of biological and cellular functions. This was followed by comparative analysis with the ancient genomes to identify their evolutionary patterns. Our results identified significant positive selection signals in 18 ASD risk SNPs. Functional and ontology analysis indicate the role of biological and cellular processes associated with various brain functions. The core of the biological interaction network constitutes genes for cognition and learning while genes in the periphery of the network had direct or indirect impact on brain function. Ancient genome analysis identified de novo and conserved evolutionary selection clusters. The de-novo evolutionary cluster represented genes involved in cognitive function. Relative enrichment of the ASD risk SNPs from the respective evolutionary cluster or biological interaction networks may help in addressing the phenotypic diversity in ASD. This cognitive genomic tradeoff signatures impacting the biological networks can explain the paradoxical phenotypes in ASD.

scholarly journals Impaired executive functions predict repetitive behaviors in toddlers under 36 months old with autism spectrum disorder symptoms

2021 ◽  
Author(s):  
Saeid Sadeghi ◽  
Hamid Reza Pouretemad ◽  
Reza Shervin Badv
Keyword(s):  
Autism Spectrum Disorder ◽  
Executive Functioning ◽  
Executive Functions ◽  
Rating Scale ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Future Research ◽  
Cross Sectional

Abstract Background: Executive Functions (EFs) deficit in Autism spectrum disorder (ASD) has been mainly investigated, while less is known about the EFs in toddlers. The study aimed was to investigate the relationship between EFs deficits and repetitive and restricted behaviors (RRBs) in toddlers with ASD symptoms. Finally, we examined whether EFs deficits were predictive of RRBs.Method: Cross-sectional data were collected from mothers of forty-five toddlers under 36 months old. The modified checklist for autism in toddlers (M-CHAT). The Gilliam autism rating scale (GARS-2), the behavior rating inventory of executive functioning-preschool version (BRIEF-P), and repetitive behavior scale- revised (RBS-R) administered to mothers.Findings: We found significant associations between parent-reported executive functions problems and (1) stereotyped behaviors, (2) self-injurious behaviors, (3) ritualistic behaviors, (4) sameness behaviors, (5) restricted behaviors, (6) compulsive behaviors, and (7) repetitive behaviors total score. There was a lack of association between M-CHAT and social interactions deficits of GARS-2 and the repetitive behaviors total score. Increases in the degree of EFs deficits predicted increments in repetitive behaviors.Discussion: These results support a link between executive disfunction and RRBs. Future research on RRBs in ASD may benefit from focusing on specific executive functioning abilities rather than general categories.

scholarly journals The female protective effect against autism spectrum disorder

2021 ◽  
Author(s):  
Emilie M. Wigdor ◽  
Daniel J. Weiner ◽  
Jakob Grove ◽  
Jack M. Fu ◽  
Wesley K. Thompson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Protective Effect ◽  
Rare Variants ◽  
De Novo ◽  
Autism Spectrum ◽  
High Impact ◽  
Spectrum Disorder ◽  
Polygenic Risk ◽  
Female Protective Effect ◽  
Nationally Representative

Autism spectrum disorder (ASD) is diagnosed 3-4 times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common, inherited genetic risk for ASD are less studied. Leveraging the nationally representative Danish iPSYCH resource, we found siblings of female ASD cases had higher rates of ASD than siblings of male ASD cases (P < 0.01). In the Simons Simplex and SPARK collections, mothers of ASD cases carried more polygenic risk for ASD than fathers of ASD cases (P = 7.0 ⨉ 10-7). Male unaffected siblings under-inherited polygenic risk (P = 0.03); female unaffected siblings did not. Further, female ASD cases without a high-impact de novo variant over-inherited nearly three-fold the polygenic risk of male cases with a high-impact de novo (P = 0.02). Our findings support a FPE against ASD that includes common, inherited genetic variation.

The State of Virtual and Augmented Reality Therapy for Autism Spectrum Disorder (ASD)

2019 ◽  
pp. 118-140 ◽  
Author(s):  
Sinan Turnacioglu ◽  
Joseph P McCleery ◽  
Julia Parish-Morris ◽  
Vibha Sazawal ◽  
Rita Solorzano
Keyword(s):  
Autism Spectrum Disorder ◽  
Augmented Reality ◽  
Behavioral Interventions ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Reality Therapy ◽  
Future Research ◽  
Future Research Directions ◽  
Number Of Individuals

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition affecting a growing number of individuals across the lifespan. It is characterized by observable impairments in social communication, as well as repetitive behaviors and restricted patterns of interests. Early, intensive behavioral interventions improve long-term outcomes in ASD, but are often expensive and hard to administer consistently. This chapter describes a new approach to autism intervention, using highly motivating virtual reality (VR) and augmented reality (AR) technologies that could soon support traditional autism therapies across ages and ability levels. The chapter begins by reviewing the ASD phenotype, followed by a review of the current landscape of research on VR and AR in ASD. A discussion of ASD-specific benefits and risks is followed by a presentation of new, harnessed immersive VR technology from Floreo, Inc. Finally, we propose a series of future research directions.

Sign in / Sign up

Export Citation Format

Share Document