scholarly journals Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Lin Wang ◽  
Yi Zhang ◽  
Kuokuo Li ◽  
Zheng Wang ◽  
Xiaomeng Wang ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Expression Patterns ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Functional Relationships ◽  
Whole Exome Sequencing Data

Abstract Background Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs). Methods We used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns. Results Among the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be enriched in these functional clusters compared with DNGs. Furthermore, although RIGs and DNGs presented comparable expression patterns in the human brain, RIGs were less likely to be associated with prenatal brain regions, the middle cortical layers, and excitatory neurons than DNGs. Limitations The RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD. Conclusions ASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.

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 Transcriptional subtyping explains phenotypic variability in genetic subtypes of autism spectrum disorder

2020 ◽  
Vol 32 (4) ◽  
pp. 1353-1361
Author(s):  
Sandy Trinh ◽  
Anne Arnett ◽  
Evangeline Kurtz-Nelson ◽  
Jennifer Beighley ◽  
Marta Picoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Communication ◽  
Phenotypic Variability ◽  
Expression Patterns ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Phenotypic Heterogeneity ◽  
Spectrum Disorder ◽  
Genetic Subtypes

AbstractAutism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in social communication and presence of restricted, repetitive behaviors, and interests. However, individuals with ASD vary significantly in their challenges and abilities in these and other developmental domains. Gene discovery in ASD has accelerated in the past decade, and genetic subtyping has yielded preliminary evidence of utility in parsing phenotypic heterogeneity through genomic subtypes. Recent advances in transcriptomics have provided additional dimensions with which to refine genetic subtyping efforts. In the current study, we investigate phenotypic differences among transcriptional subtypes defined by neurobiological spatiotemporal co-expression patterns. Of the four transcriptional subtypes examined, participants with mutations to genes typically expressed highly in all brain regions prenatally, and those with differential postnatal cerebellar expression relative to other brain regions, showed lower cognitive and adaptive skills, higher severity of social communication deficits, and later acquisition of speech and motor milestones, compared to those with mutations to genes highly expressed during the postnatal period across brain regions. These findings suggest higher-order characterization of genetic subtypes based on neurobiological expression patterns may be a promising approach to parsing phenotypic heterogeneity among those with ASD and related neurodevelopmental disorders.

scholarly journals Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Chuphong Thongnak ◽  
Areerat Hnoonual ◽  
Duangkamol Tangviriyapaiboon ◽  
Suchaya Silvilairat ◽  
Apichaya Puangpetch ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Bioinformatics Pipeline ◽  
Whole Exome ◽  
De Novo Variant ◽  
Genetic Analyzer

Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals Graph Ricci Curvatures Reveal Disease-related Changes in Autism Spectrum Disorder

2021 ◽  
Author(s):  
Pavithra Elumalai ◽  
Yasharth Yadav ◽  
Nitin Williams ◽  
Emil Saucan ◽  
Jürgen Jost ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Resting State ◽  
Neurodevelopmental Disorders ◽  
Data Exchange ◽  
Meta Analysis ◽  
Resting State Fmri ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
The Brain

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders that pose a significant global health burden. Measures from graph theory have been used to characterise ASD-related changes in resting-state fMRI functional connectivity networks (FCNs), but recently developed geometry-inspired measures have not been applied so far. In this study, we applied geometry-inspired graph Ricci curvatures to investigate ASD-related changes in resting-state fMRI FCNs. To do this, we applied Forman-Ricci and Ollivier-Ricci curvatures to compare networks of ASD and healthy controls (N = 1112) from the Autism Brain Imaging Data Exchange I (ABIDE-I) dataset. We performed these comparisons at the brain-wide level as well as at the level of individual brain regions, and further, determined the behavioral relevance of region-specific differences with Neurosynth meta-analysis decoding. We found brain-wide ASD-related differences for both Forman-Ricci and Ollivier-Ricci curvatures. For Forman-Ricci curvature, these differences were distributed across 83 of the 200 brain regions studied, and concentrated within the Default Mode, Somatomotor and Ventral Attention Network. Meta-analysis decoding identified the brain regions showing curvature differences as involved in social cognition, memory, language and movement. Notably, comparison with results from previous non-invasive stimulation (TMS/tDCS) experiments revealed that the set of brain regions showing curvature differences overlapped with the set of brain regions whose stimulation resulted in positive cognitive or behavioural outcomes in ASD patients. These results underscore the utility of geometry-inspired graph Ricci curvatures in characterising disease-related changes in ASD, and possibly, other neurodevelopmental disorders.

scholarly journals Evaluation of circulating miRNAs and mRNAs expression patterns in autism spectrum disorder

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Amany H. Abdelrahman ◽  
Ola M. Eid ◽  
Mona H. Ibrahim ◽  
Safa N. Abd El-Fattah ◽  
Maha M. Eid ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gene Family ◽  
Complex Disease ◽  
Expression Patterns ◽  
Normal Volunteer ◽  
Disease Diagnosis ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Expression Levels ◽  
Significant Difference

Abstract Background Autism spectrum disorder is a condition related to brain development that affects a person’s perception and socialization, resulting in problems in social interaction and communication. It has no single known cause, yet several different genes appear to be involved in autism. As a genetically complex disease, dysregulation of miRNA expression and miRNA–mRNA interactions might be a feature of autism spectrum disorder. The aim of the current study was to investigate the expression profile of circulating miRNA-128, miRNA-7 and SHANK gene family in ASD patients and to assess the possible influence of miRNA-128 and miRNA-7 on SHANK genes, which might provide an insight into the pathogenic mechanisms of ASD and introduce noninvasive molecular biomarkers for the disease diagnosis and prognosis. Quantitative real-time PCR technique was employed to determine expression levels of miRNA-128, miRNA-7 and SHANK gene family in blood samples of 40 autistic cases along with 30 age- and sex-matched normal volunteer subjects. Results Our study revealed a statistical significant upregulation of miRNA-128 expression levels in ASD cases compared to controls (p value < 0.001). A statistical significant difference in SHANK-3 expression was encountered on comparing cases to controls (p value < 0.001). However, miRNA-7 expression showed no significant difference between the studied groups. Conclusions MiRNA-128 and SHANK-3 gene are emerging players in the field of ASD. They are promising candidates as noninvasive biomarkers in autism. Future studies are needed to emphasize their pivotal role.

scholarly journals Increased burden of deleterious variants in essential genes in autism spectrum disorder

2016 ◽  
Vol 113 (52) ◽  
pp. 15054-15059 ◽  
Author(s):  
Xiao Ji ◽  
Rachel L. Kember ◽  
Christopher D. Brown ◽  
Maja Bućan
Keyword(s):  
Autism Spectrum Disorder ◽  
Large Scale ◽  
De Novo ◽  
Autism Spectrum ◽  
Essential Genes ◽  
Spectrum Disorder ◽  
Model Organisms ◽  
Disease Genes ◽  
Priority List ◽  
Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

Executive Functions in Adolescents with Autism Spectrum Disorder

2017 ◽  
pp. 67-90
Author(s):  
Yael Dai ◽  
Inge-Marie Eigsti
Keyword(s):  
Autism Spectrum Disorder ◽  
Working Memory ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Clinical Implications ◽  
Future Directions ◽  
Adolescents With Autism ◽  
Memory Flexibility ◽  
The Brain

This chapter reviews strengths and weaknesses in executive function (EF) domains, including inhibition, working memory, flexibility, fluency, and planning, in adolescents (age 13–19) with autism spectrum disorder (ASD). Given the dramatic developmental changes in the brain regions that support EF during the period of adolescence, it is critical to evaluate which EF abilities show a distinct profile during this period. As this chapter will demonstrate, youth with ASD show deficits across all domains of EF, particularly in complex tasks that include arbitrary instructions. We describe the fundamental measures for assessing skills in each domain and discuss limitations and future directions for research, as well as clinical implications of these findings for working with youth with ASD.

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