scholarly journals Epigenomic convergence of genetic and immune risk factors in neurodevelopmental disorder cortex

2018 ◽  
Author(s):  
Vogel Ciernia A. ◽  
Laufer B.I. ◽  
Dunaway K.W. ◽  
Hwang H. ◽  
Mordaunt C.E. ◽  
...  
Keyword(s):  
Risk Factors ◽  
Gene Networks ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Cell Types ◽  
Developed Countries ◽  
Autism Spectrum ◽  
Regulatory Regions ◽  
Human Cortex ◽  
Genes And Environment

AbstractNeurodevelopmental disorders (NDDs) impact 7% to 14% of all children in developed countries and are one of the leading causes of lifelong disability. Epigenetic modifications are poised at the interface between genes and environment and are predicted to reveal insight into the gene networks, cell types, and developmental timing of NDD etiology. Whole-genome bisulfite sequencing was used to examine DNA methylation in 49 human cortex samples from three different NDDs (autism spectrum disorder, Rett syndrome, and Dup15q syndrome) and matched controls. Integration of methylation differences across NDDs with relevant genomic and genetic datasets revealed differentially methylated regions (DMRs) unique to each type of NDD but with shared regulatory functions in neurons and microglia. DMRs were significantly enriched for known NDD genetic risk factors, including both common inherited and rare de novo variants. Weighted region co-methylation network analysis revealed a module related to NDD diagnosis and enriched for microglial regulatory regions. Together, these results demonstrate an epigenomic signature of NDDs in human cortex shared with known genetic and immune etiological risk. Epigenomic insights into cell types and gene regulatory regions will aid in defining therapeutic targets and early biomarkers at the interface of genetic and environmental NDD risk factors.

scholarly journals Epigenomic Convergence of Neural-Immune Risk Factors in Neurodevelopmental Disorder Cortex

2019 ◽  
Vol 30 (2) ◽  
pp. 640-655 ◽  
Author(s):  
A Vogel Ciernia ◽  
B I Laufer ◽  
H Hwang ◽  
K W Dunaway ◽  
C E Mordaunt ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cytosine Methylation ◽  
System Development ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
Developed Countries ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Human Cortex ◽  
Genes And Environment

Abstract Neurodevelopmental disorders (NDDs) affect 7–14% of all children in developed countries and are one of the leading causes of lifelong disability. Epigenetic modifications are poised at the interface between genes and environment and are predicted to reveal insight into NDD etiology. Whole-genome bisulfite sequencing was used to examine DNA cytosine methylation in 49 human cortex samples from 3 different NDDs (autism spectrum disorder, Rett syndrome, and Dup15q syndrome) and matched controls. Integration of methylation changes across NDDs with relevant genomic and genetic datasets revealed differentially methylated regions (DMRs) unique to each type of NDD but with shared regulatory functions in neurons and microglia. NDD DMRs were enriched within promoter regions and for transcription factor binding sites with identified methylation sensitivity. DMRs from all 3 disorders were enriched for ontologies related to nervous system development and genes with disrupted expression in brain from neurodevelopmental or neuropsychiatric disorders. Genes associated with NDD DMRs showed expression patterns indicating an important role for altered microglial function during brain development. These findings demonstrate an NDD epigenomic signature in human cortex that will aid in defining therapeutic targets and early biomarkers at the interface of genetic and environmental NDD risk factors.

scholarly journals The Changing Epidemiology of Autism Spectrum Disorders

2017 ◽  
Vol 38 (1) ◽  
pp. 81-102 ◽  
Author(s):  
Kristen Lyall ◽  
Lisa Croen ◽  
Julie Daniels ◽  
M. Daniele Fallin ◽  
Christine Ladd-Acosta ◽  
...  
Keyword(s):  
Risk Factors ◽  
De Novo ◽  
Endocrine Disrupting Chemicals ◽  
Developed Countries ◽  
Autism Spectrum ◽  
Environment Interaction ◽  
De Novo Mutations ◽  
Potential Risk Factors ◽  
Metabolic Conditions ◽  
Genetic And Environmental Factors

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.

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 SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

2021 ◽  
Author(s):  
Kan Yang ◽  
Yuhan Shi ◽  
Xiujuan Du ◽  
Yuefang Zhang ◽  
Shifang Shan ◽  
...  
Keyword(s):  
Social Interaction ◽  
De Novo ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genetic Components ◽  
Truncating Mutation ◽  
Synaptic Functions ◽  
Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

scholarly journals Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

2021 ◽  
Author(s):  
Xueya Zhou ◽  
Pamela Feliciano ◽  
Tianyun Wang ◽  
Irina Astrovskaya ◽  
Chang Shu ◽  
...  
Keyword(s):  
Genetic Risk ◽  
De Novo ◽  
Meta Analysis ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Moderate Risk ◽  
Full Spectrum ◽  
Risk Genes ◽  
Biological Parents

AbstractDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

Early Life Origins of ASD and ADHD

2021 ◽  
Author(s):  
Yuelong Ji ◽  
Ramkripa Raghavan ◽  
Xiaobin Wang
Keyword(s):  
Risk Factors ◽  
Early Life ◽  
Neurodevelopmental Disorder ◽  
Repetitive Behavior ◽  
Density Lipoprotein ◽  
Cost Effective ◽  
Autism Spectrum ◽  
Male Dominance ◽  
High Rate ◽  
Shared Risk

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication and by the presence of restrictive, repetitive behavior. Attention deficit hyperactivity disorder (ADHD) is another common lifelong neurodevelopmental disorder characterized by three major presentations: predominantly hyperactive/impulsive, predominantly inattentive, and combined. Although ASD and ADHD are different clinical diagnoses, they share various common characteristics, including male dominance, early childhood onset, links to prenatal and perinatal factors, common comorbidity for each other, and, often, persistence into adulthood. They also have both unique and shared risk factors, which originate in early life and have lifelong implications on the affected individuals and families and society. While genetic factors contribute to ASD and ADHD risk, the environmental contribution to ASD and ADHD has been recognized as having potentially equal importance, which raises the hope for early prevention and intervention. Maternal folate levels, maternal metabolic syndrome, and metabolic biomarkers have been associated with the risk of childhood ASD; while maternal high-density lipoprotein, maternal psychosocial stress, and in utero exposure to opioids have been associated with the risk of childhood ADHD. As for shared factors, male sex, preterm birth, placental pathology, and early life exposure to acetaminophen have been associated with both ASD and ADHD. The high rate of comorbidity of ASD and ADHD and their many shared early life risk factors suggest that early identification and intervention of common early life risk factors may be cost-effective to lower the risk of both conditions. Efforts to improve maternal preconception, prenatal, and perinatal health will not only help reduce adverse reproductive and birth outcomes but will also help mitigate the risk of ASD and ADHD associated with those adverse early life events.

scholarly journals Research of the Causes and Risk Factors of Autism in the Western Region of Algeria

2020 ◽  
Vol 10 (6) ◽  
pp. 91-98
Author(s):  
Hayet Mehida ◽  
Samira Meziani ◽  
Wahiba Mehida ◽  
Khalida Zemri ◽  
Imene Bekhaled ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Symptoms ◽  
Neurodevelopmental Disorder ◽  
Fetal Distress ◽  
Autism Spectrum ◽  
Western Region ◽  
Male Predominance ◽  
Autism Spectrum Disorder Risk ◽  
The Western Region ◽  
Causes And Risk Factors

Introduction Autism is a neurodevelopmental disorder that manifests before 3 years old and affects many areas, communication, social interactions and behaviors. In Algeria, there has not yet been a regional or national epidemiological investigation concerning autism spectrum disorders. Materials and methods: Our study was carried about 100 patients ( autistic children) in the western region of Algeria, in order to determine the differents risk factors involved in the onset of autism syndrome. Results and discussion: The obtained results indicate a male predominance with a sex ratio of 4: 1 and the degree of reached is average in 44% of patients. 42% of the patients are youngsters. Parents' worry about their children begins  between 24 and 36 months. The parents' advanced age at conception, stress, presence of certain pathologies and drug intake by mothers, as well as fetal distress at birth and children's exposure to screens were the main risk factors. Repetitive movements, lack of social communication, language delay, and lack of visual fixation were the main clinical symptomatology. Conclusion: This study allowed us to detect the main factors associated with the onset of autism. However, the results obtained cannot be generalized to the entire population. Keywords: Autism, autism spectrum disorder, risk factors, clinical symptoms, western region of Algeria.

scholarly journals Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

2021 ◽  
Vol 7 (1) ◽  
pp. e551
Author(s):  
Jennifer M. Bain ◽  
Olivia Thornburg ◽  
Cheryl Pan ◽  
Donnielle Rome-Martin ◽  
Lia Boyle ◽  
...  
Keyword(s):  
Language Impairment ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Retrospective Chart Review ◽  
Premature Death ◽  
Parent Report ◽  
Autism Spectrum ◽  
Pathogenic Variants ◽  
Motor Problems ◽  
Cortical Visual Impairment

ObjectiveTo expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.MethodsParticipants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.ResultsWe expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2–38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.ConclusionsThe spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

scholarly journals Translational animal models of autism and neurodevelopmental disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 293-305 ◽  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Homologous Genes ◽  
Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

scholarly journals Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Nasna Nassir ◽  
Asma Bankapur ◽  
Bisan Samara ◽  
Abdulrahman Ali ◽  
Awab Ahmed ◽  
...  
Keyword(s):  
Single Cell ◽  
Large Scale ◽  
De Novo ◽  
Cell Types ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome ◽  
Variant Genes

Abstract Background In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of ‘brain to behaviour’ pathogenic mechanisms, remains largely unknown. Methods We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single-cell transcriptomes (> million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases). Results We identified multiple single-cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed significant enrichment with ASD loss-of-function variant genes (p < 5.23 × 10–11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p < 6.40 × 10–11, oligodendrocyte, p < 1.31 × 10–09). Conclusion Among the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder.

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