Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these ...disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive ...behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable (∼90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
The goal of this study was to describe the typical longitudinal developmental trajectories of social and communication functioning in children with autism and to determine the correlates of these ...trajectories.
Children with autism who were born in California from 1992 through 2001 and enrolled with the California Department of Developmental Services were identified. Subjects with <4 evaluations present in the database were excluded, resulting in a sample of 6975 children aged 2 to 14 years. Score sequences were constructed based on 9 evaluative items for social, communication, and repetitive behavior functioning. Typical trajectories were identified by using group-based latent trajectory modeling, and multinomial logistic regression models were used to determine the odds of classification within each trajectory varied by individual and family-level factors.
Six typical patterns of social, communication, and repetitive behavior functioning were identified. These trajectories displayed significant heterogeneity in developmental pathways, and children whose symptoms were least severe at first diagnosis tended to improve more rapidly than those severely affected. One group of ∼10% of children experienced rapid gains, moving from severely affected to high functioning. Socioeconomic factors were correlated with trajectory outcomes; children with non-Hispanic, white, well-educated mothers were more likely to be high functioning, and minority children with less-educated mothers or intellectual disabilities were very unlikely to experience rapid gains.
Children with autism have heterogeneous developmental pathways. One group of children evidenced remarkable developmental change over time. Understanding what drives these outcomes is thus critical.
Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification ...may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.
Display omitted
•Resequencing ASD patients identifies a cohort defined genotypically by CHD mutations•Rephenotyping the CHD8 cohort indicates common morphological and GI features•CHD8 disruption in zebrafish recapitulates aspects of the human phenotype
Identification of patients all harboring mutations in the ASD risk gene CHD8 revealed common phenotypes among them, indicating that CHD8 disruptions define a distinct ASD subtype characterized, in part, by macrocephaly and impaired gastrointestinal function.
Symptom severity and adaptive functioning are fundamental domains of the autism spectrum disorder (ASD) phenotype. To date, the longitudinal association between these 2 domains has not been examined.
...To describe the developmental trajectories of autistic symptom severity and adaptive functioning in a large inception cohort of preschool children with ASD.
The sample consisted of 421 newly diagnosed preschool children with ASD 2 to 4 years old (355 boys; mean age at study enrollment, 39.87 months) participating in a large Canadian multisite longitudinal study (Pathways in ASD Study). Prospective data collected at 4 points from time of diagnosis to age 6 years were used to track the developmental trajectories of children.
Autistic symptom severity was indexed using the Autism Diagnostic Observation Schedule. Adaptive functioning was indexed using the Vineland Adaptive Behavior Scales, Second Edition.
Two distinct trajectory groups provided the best fit to the autistic symptom severity data. Group 1 (11.4% of the sample) had less severe symptoms and an improving trajectory (P < .05), whereas group 2 (88.6% of the sample) had more severe symptoms and a stable trajectory. Three distinct trajectory groups provided the best fit to the adaptive functioning data. Group 1 (29.2% of the sample) showed lower functioning and a worsening trajectory, group 2 (49.9% of the sample) had moderate functioning and a stable trajectory, and group 3 (20.9% of the sample) had higher functioning and an improving trajectory (P < .05). Cross-trajectory overlap between the autistic symptom severity and adaptive functioning groups was low (φ = 0.13, P < .05). Sex was a significant predictor of autistic symptom severity group membership and age at diagnosis, and language and cognitive scores at baseline predicted membership in adaptive functioning trajectories. Trajectories of both symptom severity and adaptive functioning predicted several different outcomes at age 6 years.
Findings confirm the heterogeneous nature of developmental trajectories in ASD. Change in adaptive functioning suggests that improvement is possible in roughly 20% of the sample. Autistic symptom severity appears to be more stable, with roughly 11% of the sample showing a marked decrease in symptom severity. During the preschool years, there appears to be only a small amount of "yoking" of developmental trajectories in autistic symptom severity and adaptive functioning. It is imperative that a flexible suite of interventions that target both autistic symptom severity and adaptive functioning should be implemented and tailored to each child's strengths and difficulties.
The expression of autism spectrum disorder (ASD) is highly heterogeneous, owing to the complex interactions between genes, the brain, and behavior throughout development. Here we present a model of ...ASD that implicates an early and initial failure to develop the specialized functions of one or more of the set of neuroanatomical structures involved in social information processing (i.e., the ‘social brain’). From this early and primary disruption, abnormal brain development is canalized because the individual with an ASD must develop in a highly social world without the specialized neural systems that would ordinarily allow him or her to partake in the fabric of social life, which is woven from the thread of opportunities for social reciprocity and the tools of social engagement. This brain canalization gives rise to other characteristic behavioral deficits in ASD including deficits in communication, restricted interests, and repetitive behaviors. We propose that focused efforts to explore the brain mechanisms underlying the core, pathognomic deficits in the development of mechanisms for social engagement in ASD will greatly elucidate our understanding and treatment of this complex, devastating family of neurodevelopmental disorders. In particular, developmental studies (i.e., longitudinal studies of young children with and without ASD, as well as infants at increased risk for being identified with ASD) of the neural circuitry supporting key aspects of social information processing are likely to provide important insights into the underlying components of the full‐syndrome of ASD. These studies could also contribute to the identification of developmental brain endophenotypes to facilitate genetic studies. The potential for this kind of approach is illustrated via examples of functional neuroimaging research from our own laboratory implicating the posterior superior temporal sulcus (STS) as a key player in the set of neural structures giving rise to ASD.
Abstract Animal models indicate that maternal infection during pregnancy can result in behavioral abnormalities and neuropathologies in offspring. We examined the association between maternal ...inpatient diagnosis with infection during pregnancy and risk of ASD in a Swedish nationwide register-based birth cohort born 1984–2007 with follow-up through 2011. In total, the sample consisted of 2,371,403 persons with 24,414 ASD cases. Infection during pregnancy was defined from ICD codes. In the sample, 903 mothers of ASD cases (3.7%) had an inpatient diagnosis of infection during pregnancy. Logistic regression models adjusted for a number of covariates yielded odds ratios indicating approximately a 30% increase in ASD risk associated with any inpatient diagnosis of infection. Timing of infection did not appear to influence risk in the total Swedish population, since elevated risk of ASD was associated with infection in all trimesters. In a subsample analysis, infections were associated with greater risk of ASD with intellectual disability than for ASD without intellectual disability. The present study adds to the growing body of evidence, encompassing both animal and human studies, that supports possible immune-mediated mechanisms underlying the etiology of ASD.
The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR ...SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3–12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h ² = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the “G” allele of rs53576 showed impaired affect recognition performance and carriers of the “A” allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.
Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same ...time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.
PDF
