Correction of Batch Effect in Gut Microbiota Profiling of ASD Cohorts from Different Geographical Origins.

BACKGROUND: To date, there have been numerous metataxonomic studies on gut microbiota (GM) profiling based on the analyses of data from public repositories. However, differences in study population and wet and dry pipelines have produced discordant results. Herein, we propose a biostatistical approach to remove these batch effects for the GM characterization in the case of autism spectrum disorders (ASDs). METHODS: An original dataset of GM profiles from patients with ASD was ecologically characterized and compared with GM public digital profiles of age-matched neurotypical controls (NCs). Also, GM data from seven case-control studies on ASD were retrieved from the NCBI platform and exploited for analysis. Hence, on each dataset, conditional quantile regression (CQR) was performed to reduce the batch effects originating from both technical and geographical confounders affecting the GM-related data. This method was further applied to the whole dataset matrix, obtained by merging all datasets. The ASD GM markers were identified by the random forest (RF) model. RESULTS: We observed a different GM profile in patients with ASD compared with NC subjects. Moreover, a significant reduction of technical- and geographical-dependent batch effects in all datasets was achieved. We identified Bacteroides_H, Faecalibacterium, Gemmiger_A_73129, Blautia_A_141781, Bifidobacterium_388775, and Phocaeicola_A_858004 as robust GM bacterial biomarkers of ASD. Finally, our validation approach provided evidence of the validity of the QCR method, showing high values of accuracy, specificity, sensitivity, and AUC-ROC. CONCLUSIONS: Herein, we proposed an updated biostatistical approach to reduce the technical and geographical batch effects that may negatively affect the description of bacterial composition in microbiota studies.

Elimination of the extra chromosome of Dup15q syndrome iPSCs for cellular and molecular investigation.

Chromosome 15q11.2-13.1 duplication (Dup15q) syndrome is one of the most common autism spectrum disorders (ASDs) associated with copy number variants (CNVs). For the analysis of CNV-relevant pathological cellular phenotypes, a CNV-corrected isogenic cell line is useful for excluding the influence of genetic background. Here, we devised a strategy to remove the isodicentric chromosome 15 by inserting a puro-ΔTK selection cassette into the extra chromosome using the CRISPR-Cas9 system, followed by a subsequent two-step drug selection. A series of assays, including qPCR-based copy number analysis and karyotype analysis, confirmed the elimination of the extra chromosome. Furthermore, cerebral organoids were generated from the parental Dup15q iPSCs and their isogenic iPSCs. scRNA-seq analysis revealed the alteration of expression levels in ion-channel-related genes and synapse-related genes in glutamatergic and GABAergic neurons in Dup15q organoids, respectively. The established isogenic cell line is a valuable resource for unraveling cellular and molecular alterations associated with Dup15q syndrome.

Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome.

The number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and the most common monogenetic inheritable form of ASDs is Fragile X Syndrome (FXS). Previous studies indicate that FXS is linked to glutamate signaling regulation by the G-protein-coupled metabotropic glutamate receptor 5 (mGluR5), which has been shown to have a regulatory role in neuroinflammation. We characterized the effect of knocking out mGluR5 in an organism known to have complex cognitive functions-the rat. The heterozygous phenotype is the most clinically relevant; therefore, we performed analysis in heterozygous pups. We showed developmental abnormalities in heterozygous mGluR5 knockout rats, as well as a significant increase in chemokine (C-X-C motif) ligand 1 (CXCL) expression, a hallmark indicator of early onset inflammation. We quantified an increase in microglial density in the knockout pups and quantified morphological phenotypes representative of greater reactivity in the male vs. female and postnatal day 28 heterozygous pups compared to postnatal day 14 heterozygous pups. In response to injury, reactive microglia release matrix metalloproteases, contribute to extracellular matrix (ECM) breakdown, and are responsible for eradicating cellular and molecular debris. In our study, the changes in microglial density and reactivity correlated with abnormalities in the mRNA expression levels of ECM proteins and with the density of perineuronal nets. We saw atypical neuropsychiatric behavior in open field and elevated plus tests in heterozygous pups compared to wild-type litter and age-matched controls. These results demonstrate the pathological potential of the mGluR5 knockout in rats and further support the presence of neuroinflammatory roots in ASDs.

auts2 Features and Expression Are Highly Conserved during Evolution Despite Different Evolutionary Fates Following Whole Genome Duplication.

The AUTS2 gene plays major roles during brain development and is associated with various neuropathologies including autism. Data in non-mammalian species are scarce, and the aim of our study was to provide a comprehensive analysis of auts2 evolution in teleost fish, which are widely used for in vivo functional analysis and biomedical purposes. Comparative genomics in 78 species showed that auts2a and auts2b originate from the teleost-specific whole genome duplication (TGD). auts2a, which is highly similar to human AUTS2, was almost systematically retained following TGD. In contrast, auts2b, which encodes for a shorter protein similar to a short human AUTS2 isoform, was lost more frequently and independently during evolution. RNA-seq analysis in 10 species revealed a highly conserved profile with predominant expression of both genes in the embryo, brain, and gonads. Based on protein length, conserved domains, and expression profiles, we speculate that the long human isoform functions were retained by auts2a, while the short isoform functions were retained by auts2a and/or auts2b, depending on the lineage/species. auts2a showed a burst in expression during medaka brain formation, where it was expressed in areas of the brain associated with neurodevelopmental disorders. Together, our data suggest a strong conservation of auts2 functions in vertebrates despite different evolutionary scenarios in teleosts.

Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report.

Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders and occurs in all racial, ethnic, and socioeconomic groups. Cutting-edge technologies are contributing to understanding genetic underpinnings in ASD. The reported patient is a 32-year-old male and as an infant was noted to have microcephaly, hypospadias, pulmonary vascular anomaly, and small stature. He was diagnosed with Cornelia De Lange Syndrome (CDLS) at that time based on the clinical features. As a child, he had autistic features and intellectual disabilities and as diagnoses with autism and intellectual disability. He was referred as an adult to our neurodiversity clinic and a full exome trio sequencing with reflex to mitochondrial genes identified a de novo variant of uncertain significance in a candidate gene, DCAF1. The specific variant was c.137 C > T (p.Thr46Ile) in exon 4 in the DCAF1 gene. In silico analysis supports a deleterious effect on protein structure/function. DCAF1 participates with DDB1 and CUL4 as a part of the E3 ubiquitin ligase complex. The E3 ligase complex has been associated with a syndromic form of X-linked intellectual disability. The DDB1/CUL4 E3 ubiquitination complex plays a role in methylation-dependent ubiquitination. Next, a methylation study identified a signature similar to the methylation pattern found in X- linked intellectual disability type 93. This is associated with variants of the BRWD3 gene, which is linked with the functioning of the DDB1/CUL4 E3 ubiquitination complex. Taken together, this suggests that the de novo DCAF1 variant may be a newly identified molecular cause of autism and intellectual disability.

Globally elevated excitation-inhibition ratio in children with autism spectrum disorder and below-average intelligence.

BACKGROUND: Altered neuronal excitation-inhibition (E-I) balance is strongly implicated in ASD. However, it is not known whether the direction and degree of changes in the E-I ratio in individuals with ASD correlates with intellectual disability often associated with this developmental disorder. The spectral slope of the aperiodic 1/f activity reflects the E-I balance at the scale of large neuronal populations and may uncover its putative alternations in individuals with ASD with and without intellectual disability. METHODS: Herein, we used magnetoencephalography (MEG) to test whether the 1/f slope would differentiate ASD children with average and below-average (< 85) IQ. MEG was recorded at rest with eyes open/closed in 49 boys with ASD aged 6-15 years with IQ ranging from 54 to 128, and in 49 age-matched typically developing (TD) boys. The cortical source activity was estimated using the beamformer approach and individual brain models. We then extracted the 1/f slope by fitting a linear function to the log-log-scale power spectra in the high-frequency range. RESULTS: The global 1/f slope averaged over all cortical sources demonstrated high rank-order stability between the two conditions. Consistent with previous research, it was steeper in the eyes-closed than in the eyes-open condition and flattened with age. Regardless of condition, children with ASD and below-average IQ had flatter slopes than either TD or ASD children with average or above-average IQ. These group differences could not be explained by differences in signal-to-noise ratio or periodic (alpha and beta) activity. LIMITATIONS: Further research is needed to find out whether the observed changes in E-I ratios are characteristic of children with below-average IQ of other diagnostic groups. CONCLUSIONS: The atypically flattened spectral slope of aperiodic activity in children with ASD and below-average IQ suggests a shift of the global E-I balance toward hyper-excitation. The spectral slope can provide an accessible noninvasive biomarker of the E-I ratio for making objective judgments about treatment effectiveness in people with ASD and comorbid intellectual disability.

Prenatal, perinatal, and postnatal factors associated with autism spectrum disorder cases in Xuzhou, China.

BACKGROUND: The aim of the present study was to explore the prenatal, perinatal, and postnatal risk factors in children with autism spectrum disorder (ASD) from Xuzhou, China by comparing them with healthy children. METHODS: Children with ASD who received rehabilitation training at special education schools and rehabilitation institutions in Xuzhou were selected as the ASD group, and healthy children during the same period were selected as the healthy non-ASD group. A questionnaire based on the possible causes and susceptibility factors of ASD in children was issued and given to all children in this study. RESULTS: The findings of the present study revealed a higher prevalence of prenatal, perinatal, and postnatal factors in children with ASD compared with healthy children. There were significantly more males than females in the ASD group, and the proportion of boys to girls was 5.81:1 (P<0.05). Logistic regression analysis suggested that the risk factors of male children developing ASD were feeding difficulties, poor living environment during pregnancy, maternal exposure to cigarette smoking during pregnancy, and perinatal hypoxia. Factors associated with ASD risk among were identified, such as living environment during pregnancy, delivery method, feeding difficulties, and epilepsy (P<0.05). Feeding difficulties and living in the countryside during pregnancy might be risk factors for ASD in girls according to the logistic regression analysis. CONCLUSIONS: This survey confirmed the high prevalence of prenatal, perinatal, and postnatal factors in children with ASD. Some of these factors may be effective entry points for the prevention and treatment of ASD.

Proteomics and Metabolomics Approaches towards a Functional Insight onto AUTISM Spectrum Disorders: Phenotype Stratification and Biomarker Discovery.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by behavioral alterations and currently affect about 1% of children. Significant genetic factors and mechanisms underline the causation of ASD. Indeed, many affected individuals are diagnosed with chromosomal abnormalities, submicroscopic deletions or duplications, single-gene disorders or variants. However, a range of metabolic abnormalities has been highlighted in many patients, by identifying biofluid metabolome and proteome profiles potentially usable as ASD biomarkers. Indeed, next-generation sequencing and other omics platforms, including proteomics and metabolomics, have uncovered early age disease biomarkers which may lead to novel diagnostic tools and treatment targets that may vary from patient to patient depending on the specific genomic and other omics findings. The progressive identification of new proteins and metabolites acting as biomarker candidates, combined with patient genetic and clinical data and environmental factors, including microbiota, would bring us towards advanced clinical decision support systems (CDSSs) assisted by machine learning models for advanced ASD-personalized medicine. Herein, we will discuss novel computational solutions to evaluate new proteome and metabolome ASD biomarker candidates, in terms of their recurrence in the reviewed literature and laboratory medicine feasibility. Moreover, the way to exploit CDSS, performed by artificial intelligence, is presented as an effective tool to integrate omics data to electronic health/medical records (EHR/EMR), hopefully acting as added value in the near future for the clinical management of ASD.

Integrated Functional Analysis Implicates Syndromic and Rare Copy Number Variation Genes as Prominent Molecular Players in Pathogenesis of Autism Spectrum Disorders.

Autism Spectrum Disorders (ASD) are caused by disrupted neurodevelopment leading to socio-communication and behavioural abnormalities. Although genetic anomalies like Copy Number Variations (CNV) have been implicated in ASD, their overall genomic landscape and pathogenicity remain elusive. Therefore, we created a CNV map for ASD using 9337 cases and 5650 controls from SFARI database, statistically marked genomic regions with high and low frequencies of CNVs (i.e., common and rare CNV regions respectively), performed gene function enrichment for CNV genes, built functional networks, pathways and examined their expression in brain tissues. Information thus obtained were cumulatively integrated using a weighted scoring strategy to rank CNV regions by their neuro-functional attributes. Subsequently, we mapped 105 genic CNV regions across 20 chromosomes. They encompassed 537 genes, of which only 59 (11%) genes were identified with Single Nucleotide Variations (SNV) in ASD subjects through sequencing and functional studies, which indicated that diverse sets of genes were affected by CNVs and SNVs in ASD. Overall, syndromic CNV regions displayed the most prominent neuronal functions. While common CNV regions were found in loci 15q11.2, 16p11.2, 22q11.21, 15q13.2-13.3, rare CNV regions in loci 4p16.3, 9q34.3, 7q11.23, 17p11.2 contributed significantly to protein interaction networks and were highly expressed in brain. Enriched CNV genes were clustered in six functional categories with either direct roles in neurodevelopment or auxiliary roles like cellular signalling via MAPK pathway, cytoskeletal organization and transport or immune regulation. Mechanisms through which these molecular systems could independently or in combination trigger an ASD phenotype were predicted.

Vitamin and mineral status of children with autism spectrum disorder in Hainan Province of China: associations with symptoms.

Objective: This study was designed to compare the vitamin and mineral levels of children with autism spectrum disorders (ASDs) with those of age-matched typically developing (TD) children and to investigate their effects on the symptoms of autistic children. Methods: The Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS) and Gesell Developmental Scale (GDS) were completed for 274 children diagnosed with ASD. Vitamins and minerals were compared for all ASD children and 97 age-matched TD children. Serum levels of vitamin A (VA) were detected with high-performance liquid chromatography (HPLC); those of vitamin D (VD), folate, vitamin B12 (VB12), and ferritin were measured with immunoassay methods; and those of minerals were detected using atomic absorption spectrophotometry in two groups. Results: The VD and folate levels of children with ASD were significantly lower than those of TD children. The levels of calcium (Ca), magnesium (Mg), iron (Fe), and zinc (Zn) in children with ASD were significantly lower than those in TD children, and no significant difference was found in copper (Cu) levels. Correlation analysis showed that VA and Ca levels were negatively correlated with ASD symptoms. Folate, Ca, Fe and Zn were positively correlated with the GDS scores of autistic children. There were no significant interactions among VD, VB12 and ferritin and symptoms. Conclusion: We found that children with autism had more vitamin and mineral insufficiencies than TD children, and their levels were related to ASD symptoms. Therefore, it is essential to formulate a detailed nutritional evaluation for ASD children and provide timely and intensive interventions.

Co-Occurrence of ASD and ADHD Traits in an Adult Population.

Objective: ADHD and autism spectrum disorder (ASD) can be viewed as the extreme end of traits found in the general population. Clinical and genetic studies suggest that ADHD and ASD often co-occur and share genetic susceptibility. The aim of this study was to examine co-occurrence of ADHD and ASD traits in the general population. Method: In total, 334 participants were recruited from a population-based sample. Four questionnaires assessing current and retrospective ADHD and ASD traits were administered online: the Adult ADHD Self-Report Scale (ASRS) Symptom Checklist, the Wender Utah Rating Scale (WURS-25), the Broad Autism Phenotype Questionnaire (BAPQ), and the Autism Spectrum Quotient (AQ). Results: A significant correlation was found between ADHD and autistic traits. In particular, higher inattention and overall ADHD scores were associated with self-reported deficits in communication and social skills. Conclusion: Our findings are similar to results from studies on clinical populations, suggesting that ADHD and ASD might share common etiology.

Atypical Functional Connectivity of Amygdala Related to Reduced Symptom Severity in Children With Autism.

OBJECTIVE: Converging evidence indicates that brain abnormalities in autism spectrum disorders (ASDs) involve atypical network connectivity. Given the central role of social deficits in the ASD phenotype, this investigation examined functional connectivity of the amygdala-a brain structure critically involved in processing of social information-in children and adolescents with ASDs, as well as age-dependent changes and links with clinical symptoms. METHOD: Resting-state functional magnetic resonance imaging (rs-fMRI) data from 55 participants with ASDs and 50 typically developing (TD) controls, aged 7 to 17 years, were included. Groups were matched for age, gender, IQ, and head motion. Functional connectivity MRI (fcMRI) analysis was applied to examine intrinsic functional connectivity (iFC) of the amygdala, including cross-sectional tests of age-related changes. RESULTS: Direct between-group comparisons revealed reduced functional connectivity between bilateral amygdalae and left inferior occipital cortex, accompanied by greater connectivity between right amygdala and right sensorimotor cortex in the ASD group. This atypical pattern of amygdala connectivity was associated with decreased symptom severity and better overall functioning, as specifically seen in an ASD subgroup with the most atypical amygdala iFC but the least impaired social functioning. Age-related strengthening of amygdala-prefrontal connectivity, as observed in the TD group, was not detected in children with ASDs. CONCLUSION: Findings support aberrant network sculpting in ASDs, specifically atypical integration between amygdala and primary sensorimotor circuits. Paradoxical links between atypical iFC and behavioral measures suggest that abnormal amygdala functional connections may be compensatory in some individuals with ASDs.

Common Defects of Spine Dynamics and Circuit Function in Neurodevelopmental Disorders: A Systematic Review of Findings From in Vivo Optical Imaging of Mouse Models.

In vivo optical imaging is a powerful tool for revealing brain structure and function at both the circuit and cellular levels. Here, we provide a systematic review of findings obtained from in vivo imaging studies of mouse models of neurodevelopmental disorders, including the monogenic disorders fragile X syndrome, Rett syndrome, and Angelman syndrome, which are caused by genetic abnormalities of FMR1, MECP2, and UBE3A, as well as disorders caused by copy number variations (15q11-13 duplication and 22q11.2 deletion) and BTBR mice as an inbred strain model of autism spectrum disorder (ASD). Most studies visualize the structural and functional responsiveness of cerebral cortical neurons to sensory stimuli and the developmental and experience-dependent changes in these responses as a model of brain functions affected by these disorders. The optical imaging techniques include two-photon microscopy of fluorescently labeled dendritic spines or neurons loaded with fluorescent calcium indicators and macroscopic imaging of cortical activity using calcium indicators, voltage-sensitive dyes or intrinsic optical signals. Studies have revealed alterations in the density, stability, and turnover of dendritic spines, aberrant cortical sensory responses, impaired inhibitory function, and concomitant failure of circuit maturation as common causes for neurological deficits. Mechanistic hypotheses derived from in vivo imaging also provide new directions for therapeutic interventions. For instance, it was recently demonstrated that early postnatal administration of a selective serotonin reuptake inhibitor (SSRI) restores impaired cortical inhibitory function and ameliorates the aberrant social behaviors in a mouse model of ASD. We discuss the potential use of SSRIs for treating ASDs in light of these findings.

Functions of synapse adhesion molecules neurexin/neuroligins and neurodevelopmental disorders.

Neurexins and neuroligins are two distinct families of single-pass transmembrane proteins localized at pre- and postsynapses, respectively. They trans-synaptically interact with each other and induce synapse formation and maturation. Common variants and rare mutations, including copy number variations, short deletions, and single or small nucleotide changes in neurexin and neuroligin genes have been linked to the neurodevelopmental disorders, such as autism spectrum disorders (ASDs). In this review, we summarize the structure and basic synaptic function of neurexins and neuroligins, followed by behaviors and synaptic phenotypes of knock-in and knock-out mouse of these family genes. From the studies of these mice, it turns out that the effects of neurexins and neuroligins are amazingly neural circuit dependent, even within the same brain region. In addition, neurexins and neuroligins are commonly involved in the endocannabinoid signaling. These finding may provide not only insight into understanding the pathophysiology, but also the concept for strategy of therapeutic intervention for ASDs.

Monitoring of autonomic response to sociocognitive tasks during treatment in children with Autism Spectrum Disorders by wearable technologies: A feasibility study.

BACKGROUND: Autism Spectrum Disorders (ASD) represent a heterogeneous set of neurodevelopmental disorders characterized by impairments in social domain, where the autonomic nervous system (ANS) plays an important role. Several researchers have studied the ANS in ASD, during specific cognitive or sensory stimuli while few studies have examined response during social interactions. Wearable technologies can be very helpful in monitoring autonomic response in children with ASD in semi-naturalistic setting. The novelty of this study is to use such technologies to acquire physiological signals during therapeutic sessions supported by interactive "serious games" and to correlate the ANS response to the engagement of the child during sociocognitive tasks for an evaluation of the treatment effect and for the personalization of the therapy. METHOD: A wearable chest belt for electrocardiographic (ECG) signal recording was used and specific algorithms for the extraction of clinically relevant features (Heart Rate - HR, Root Mean Square of the Successive Differences - RMSSD and Respiratory Sinus Arrhythmia - RSA) were developed. Sociocognitive tasks were mediated by "serious games" implemented on two tablets, which allowed a precise coding of the behaviors of the children. A longitudinal assessment of the physiological response of the children during six months of treatment was performed. RESULTS: A link between physiological response, i.e. decrease in RMSSD and RSA, and engagement of the children during sociocognitive tasks was found. Longitudinal changes in the children's autonomic response, including a decrease of RSA during the engagement throughout the therapeutic sessions, were found. CONCLUSIONS: These results foster the feasibility of this methodology to be applied in a clinical setting for the monitoring of the ANS response of children with ASD during treatment. A larger sample of patients is needed to confirm these preliminary findings.

Multi-frequency localization of aberrant brain activity in autism spectrum disorder.

OBJECTIVE: The abnormality of intrinsic brain activity in autism spectrum disorders (ASDs) is still inconclusive. Contradictory results have been found pointing towards hyper-activity or hypo-activity in various brain regions. The present research aims to investigate the spatial and spectral signatures of aberrant brain activity in an unprecedented frequency range of 1-2884 Hz at source levels in ASD using newly developed methods. MATERIALS AND METHODS: Seven ASD subjects and age- and gender-matched controls were studied using a high-sampling rate magnetoencephalography (MEG) system. Brain activity in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low gamma (30-55 Hz), high gamma (65-90 Hz), ripples (90-200 Hz), high-frequency oscillations (HFOs, 200-1000 Hz), and very high-frequency oscillations (VHFOs, 1000-2884 Hz) was volumetrically localized and measured using wavelet and beamforming. RESULTS: In comparison to controls, ASD subjects had significantly higher odds of alpha activity (8-12 Hz) in the sensorimotor cortex (mu rhythm), and generally high-frequency activity (90-2884 Hz) in the frontal cortex. The source power of HFOs (200-1000 Hz) in the frontal cortex in ASD was significantly elevated as compared with controls. CONCLUSION: The results suggest that ASD has significantly altered intrinsic brain activity in both low- and high-frequency ranges. Increased intrinsic high-frequency activity in the frontal cortex may play a key role in ASD.

The Genetic Overlap of Attention-Deficit/Hyperactivity Disorder and Autistic-like Traits: an Investigation of Individual Symptom Scales and Cognitive markers.

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) frequently co-occur. However, due to previous exclusionary diagnostic criteria, little is known about the underlying causes of this covariation. Twin studies assessing ADHD symptoms and autistic-like traits (ALTs) suggest substantial genetic overlap, but have largely failed to take into account the genetic heterogeneity of symptom subscales. This study aimed to clarify the phenotypic and genetic relations between ADHD and ASD by distinguishing between symptom subscales that characterise the two disorders. Moreover, we aimed to investigate whether ADHD-related cognitive impairments show a relationship with ALT symptom subscales; and whether potential shared cognitive impairments underlie the genetic risk shared between the ADHD and ALT symptoms. Multivariate structural equation modelling was conducted on a population-based sample of 1312 twins aged 7-10. Social-communication ALTs correlated moderately with both ADHD symptom domains (phenotypic correlations around 0.30) and showed substantial genetic overlap with both inattention and hyperactivity-impulsivity (genetic correlation = 0.52 and 0.44, respectively). In addition to previously reported associations with ADHD traits, reaction time variability (RTV) showed significant phenotypic (0.18) and genetic (0.32) association with social-communication ALTs. RTV captured a significant proportion (24 %) of the genetic influences shared between inattention and social-communication ALTs. Our findings suggest that social-communication ALTs underlie the previously observed phenotypic and genetic covariation between ALTs and ADHD symptoms. RTV is not specific to ADHD symptoms, but is also associated with social-communication ALTs and can, in part, contribute to an explanation of the co-occurrence of ASD and ADHD.

Epigenetic mechanisms: A possible link between autism spectrum disorders and fetal alcohol spectrum disorders.

The etiology of autism spectrum disorders (ASDs) still remains unclear and seems to involve a considerable overlap between polygenic, epigenetic and environmental factors. We have summarized the current understanding of the interplay between gene expression dysregulation via epigenetic modifications and the potential epigenetic impact of environmental factors in neurodevelopmental deficits. Furthermore, we discuss the scientific controversies of the relationship between prenatal exposure to alcohol and alcohol-induced epigenetic dysregulations, and gene expression alterations which are associated with disrupted neural plasticity and causal pathways for ASDs. The review of the literature suggests that a better understanding of developmental epigenetics should contribute to furthering our comprehension of the etiology and pathogenesis of ASDs and fetal alcohol spectrum disorders.