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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Autism spectrum disorder (ASD) is characterized by a variety of social and non-social behavioral deficits. One potential mechanism that could unify this diverse profile of behaviors is slower processing speed. Seventy-six high-functioning adults with ASD were compared to 64 matched controls on standardized measures of processing speed. Participants with ASD were significantly slower on all measures, and on the composite score from the three tests (d's > 0.65). ASD participants with slower processing speeds scored higher on the ADOS Communication and Reciprocal Social Interaction scale (r = 0.34). These findings provide evidence of slower processing speeds in adults with ASD, and that this may be contributing to impairments in social communication skills. Interventions that improve processing speed might improve social communication abilities in ASD.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

This study examined differences between adults with autism spectrum disorder (ASD; N = 40) and typical community volunteers (N = 25) on measures of stressful life events, perceived stress, and biological stress response (cardiovascular and cortisol reactivity) during a novel social stress task. Additional analyses examined the relationship between stress and social functioning as measured by the Social Adjustment Scale-II and the Waisman Activities of Daily Living scale. Results indicated that adults with ASD experienced significantly more stressful life events and perceived stress, and greater systolic blood pressure reactivity than typical community volunteers. Results also indicated that perceived stress and stressful life events were significantly associated with social disability. Interventions targeting stress management might improve social function in adults with ASD.

Multiple hypotheses have been offered to explain the impaired face-processing behavior and the accompanying underlying disruptions in neural circuitry among individuals with autism. We explored the specificity of atypical face-processing activation and potential alterations to fusiform gyrus (FG) morphology as potential underlying mechanisms. Adolescents with high functioning autism (HFA) and age-matched typically developing (TD) adolescents were scanned with sMRI and fMRI as they observed human and animal faces. In spite of exhibiting comparable face recognition behavior, the HFA adolescents evinced hypo-activation throughout the face-processing system in response to unfamiliar human, but not animal, faces. They also exhibited greater activation in affective regions of the face-processing network in response to animal, but not human, faces. Importantly, this atypical pattern of activation in response to human faces was not related to atypical structural properties of the FG. This atypical neural response to human faces in autism may stem from abnormalities in the ability to represent the reward value of social (i.e. conspecific) stimuli.

More than 20?years ago, Minshew and colleagues proposed the Complex Information Processing model of autism in which the impairment is characterized as a generalized deficit involving multiple modalities and cognitive domains that depend on distributed cortical systems responsible for higher order abilities. Subsequent behavioral work revealed a related dissociation between concept formation and concept identification in autism suggesting the lack of an underlying organizational structure to manage increases in processing loads. The results of a recent study supported the impact of this relative weakness in conceptual reasoning on adaptive functioning in children and adults with autism. In this study, we provide further evidence of the difficulty relatively able older adolescents and adults with autism have with conceptual reasoning and provide evidence that this characterizes their difference from age- and ability-matched controls with typical development better than their differences in language. For verbal adults with autism, language may serve as a bootstrap or compensatory mechanism for learning but cannot overcome an inherent weakness in concept formation that makes information processing challenging as task demands increase.

Studies investigating inferential reasoning in autism spectrum disorder (ASD) have focused on the ability to make socially-related inferences or inferences more generally. Important variables for intervention planning such as whether inferences depend on physical experiences or the nature of social information have received less consideration. A measure of bridging inferences of physical causation, mental states, and emotional states was administered to older children, adolescents, and adults with and without ASD. The ASD group had more difficulty making inferences, particularly related to emotional understanding. Results suggest that individuals with ASD may not have the stored experiential knowledge that specific inferences depend upon or have difficulties accessing relevant experiences due to linguistic limitations. Further research is needed to tease these elements apart.

Facial emotion perception is significantly affected in autism spectrum disorder, yet little is known about how individuals with autism spectrum disorder misinterpret facial expressions that result in their difficulty in accurately recognizing emotion in faces. This study examined facial emotion perception in 45 verbal adults with autism spectrum disorder and 30 age- and gender-matched volunteers without autism spectrum disorder to identify patterns of emotion misinterpretation during face processing that contribute to emotion recognition impairments in autism. Results revealed that difficulty distinguishing emotional from neutral facial expressions characterized much of the emotion perception impairments exhibited by participants with autism spectrum disorder. In particular, adults with autism spectrum disorder uniquely misinterpreted happy faces as neutral, and were significantly more likely than typical volunteers to attribute negative valence to nonemotional faces. The over-attribution of emotions to neutral faces was significantly related to greater communication and emotional intelligence impairments in individuals with autism spectrum disorder. These findings suggest a potential negative bias toward the interpretation of facial expressions and may have implications for interventions designed to remediate emotion perception in autism spectrum disorder.

This study investigated the association between gastrointestinal symptoms and a broad set of emotional and behavioral concerns in 95 children with high-functioning autism and IQ scores = 80. Gastrointestinal symptoms were assessed via the Autism Treatment Network's Gastrointestinal Symptom Inventory, and data were gathered on autism symptom severity, adaptive behavior, and multiple internalizing and externalizing problems. The majority (61%) of children had at least one reported gastrointestinal symptom. Emotional and behavioral problems were also common but with a high degree of variability. Children with and without gastrointestinal problems did not differ in autism symptom severity, adaptive behavior, or total internalizing or externalizing problem scores. However, participants with gastrointestinal problems had significantly higher levels of affective problems. This finding is consistent with a small body of research noting a relationship between gastrointestinal problems, irritability, and mood problems in autism spectrum disorder. More research to identify the mechanisms underlying this relationship in autism spectrum disorder is warranted. Future research should include a medical assessment of gastrointestinal concerns, longitudinal design, and participants with a range of autism spectrum disorder severity in order to clarify the directionality of this relationship and to identify factors that may impact heterogeneity in the behavioral manifestation of gastrointestinal concerns.

People with autism spectrum disorder (ASD) often exhibit superior performance in visual search compared to others. However, most studies demonstrating this advantage have employed simple, uncluttered images with fully visible targets. We compare the performance of high-functioning adults with ASD and matched controls on a naturalistic luggage screening task. Although the two groups were equally accurate in detecting targets, the ASD adults improve in their correct elimination of target-absent bags faster than controls. This feature of their behavior is extremely important for many real-world monitoring tasks that require sustained attention for long time periods. Further analyses suggest that this improvement is attributable neither to the motor speed nor to the level of intelligence of the adults with ASD. These findings may have possible implications for employment opportunities of adult individuals with ASD.

This study used the modality shift experiment, a relatively simple reaction time measure to visual and auditory stimuli, to examine attentional shifting within and across modalities in 33 children and 42 adults with high-functioning autism as compared to matched numbers of age- and ability-matched typical controls. An exaggerated "modality shift effect" relative to the TD children occurred for the children with autism in conditions involving the reaction time when shifting from sound to light but not from light to sound. No exaggerated MSE was found for the adults with autism; rather, their responses were characterized by a generalized slowness relative to the adults with TD. These results suggest a lag in maturational development in autism in basic information processing mechanisms.

Individuals with autism spectrum disorders (ASD) spend the majority of their lives as adults, and psychosocial interventions show promise for improving outcomes in this population. This research conducted a systematic review of all peer-review studies evaluating psychosocial interventions for adults with ASD. A total of 1,217 studies were reviewed, only 13 met inclusion criteria. The majority of studies were single case studies or non-randomized controlled trials, and most focused on applied behavior analysis or social cognition training. Effects of psychosocial treatment in adults with ASD were largely positive ranging from d = 0.14-3.59, although the quantity and quality of studies is limited. There is substantial need for the rigorous development and evaluation of psychosocial treatments for adults with ASD.

A growing body of literature has identified size reductions of the corpus callosum (CC) in autism. However, to our knowledge, no published studies have reported on the growth of CC volumes in youth with autism. Volumes of the total CC and its sub-divisions were obtained from 23 male children with autism and 23 age- and gender-matched controls at baseline and 2-year follow-up. Persistent reductions in total CC volume were observed in participants with autism relative to controls. Only the rostral body subdivision showed a normalization of size over time. Persistent reductions are consistent with the diagnostic stability and life-long impairment observed in many individuals with autism. Multi-modal imaging studies are needed to identify specific fiber tracks contributing to CC reductions. (Contains 3 tables and 1 figure.)

There is a growing amount of evidence suggesting that individuals with autism have difficulty with categorization. One basic cognitive ability that may underlie this difficulty is the ability to abstract a prototype. The current study examined prototype and category formation with dot patterns in high-functioning adults with autism and matched controls. Individuals with autism were found to have difficulty forming prototypes and categories of dot patterns. The eye-tracking data did not reveal any between group differences in attention to the dot patterns. However, relationships between performance and intelligence in the autism group suggest possible processing differences between the groups. Results are consistent with previous studies that have found deficits in prototype formation and extend these deficits to dot patterns.

It has been established that typically developing individuals have a bias to attend to facial information in the left visual field (LVF) more than in the right visual field. This bias is thought to arise from the right hemisphere's advantage for processing facial information, with evidence suggesting it to be driven by the configural demands of face processing. Considering research showing that individuals with autism have impaired face processing abilities, with marked deficits in configural processing, it was hypothesized that they would not demonstrate a LVF bias for faces. Eye-tracking technology was used to show that individuals with autism were not spontaneously biased to facial information in the LVF, in contrast to a control group, while discriminating facial gender.

There is a growing amount of evidence suggesting that individuals with autism have difficulty with face processing. One basic cognitive ability that may underlie face processing difficulties is the ability to abstract a prototype. The current study examined prototype formation with natural faces using eye-tracking in high-functioning adults with autism and matched controls. Individuals with autism were found to have significant difficulty forming prototypes of natural faces. The eye-tracking data did not reveal any between group differences in the general pattern of attention to the faces, indicating that these difficulties were not due to attentional factors. Results are consistent with previous studies that have found a deficit in prototype formation and extend these deficits to natural faces.

Previous behavioral studies have shown that individuals with autism are less hindered by interference from global processing during the performance of lower-level perceptual tasks, such as finding embedded figures. The primary goal of this study was to examine the brain manifestation of such atypicality in high-functioning autism using fMRI. Fifteen participants with high-functioning autism and fifteen age- and IQ-matched typical controls were asked to perform a lower-level perceptual line-counting task in the presence of a distracting depiction of a 3-D object, in which participants counted whether there were more red or more green contours (In a contrasting 3-D task, participants judged whether the same 3-D stimulus objects (but without color in any contours) depicted a possible or impossible 3-D object). We hypothesized that individuals with autism would be less likely than controls to process the global 3-D information (and would hence show fewer neural signs of such interfering 3-D processing) during the lower-level line-counting task. The fMRI results revealed that in the line-counting task, the autism group did not show the increased medial frontal activity (relative to the possibility task), or the increased functional connectivity between the medial frontal region and posterior visual-spatial regions, demonstrated by the control group. Both findings are indices of lesser effort and difficulty in the line-counting task for the autism group than for the control group, attributed to less interference from the 3-D processing in the autism group. In addition, in the line-counting task, the control group showed a positive correlation between a measure of spatial ability (Vandenberg scores) and activation in the medial frontal region, suggesting that more spatially able control participants did more suppression of the irrelevant 3-D background information in order to focus on the line-counting task. The findings collectively indicate that the global 3-D structure of the figure had a smaller effect, if any, on local processing in the group with autism compared to the control group. The results from this study provide the first direct neural evidence of reduced global-to-local interference in autism. (Contains 5 figures and 1 table.)

Little is known regarding metacognition in individuals with autism. Specifically, it is unclear how individuals with autism think about their own mental states. The current study assessed memory awareness during a facial recognition task. High-functioning children (M = 13.1 years, n = 18) and adults (M = 27.5 years, n = 16) with autism matched with typically developing children (M = 14.3 years, n = 13) and adults (M = 26.9 years, n = 15) were tested. Children with autism demonstrated less accurate memory awareness for faces and less reliable differentiation between their confidence ratings compared to typically developing children. Subtle impairments in memory awareness for faces were also evident in adults with autism. Results indicate that broader metacognitive deficits may exist in individuals with autism, possibly contributing to other known impairments. (Contains 2 tables and 2 figures.)

The corpus callosum has recently been considered as an index of interhemispheric connectivity. This study applied a novel volumetric method to examine the size of the corpus callosum in 32 individuals with autism and 34 age-, gender- and IQ-matched controls and to investigate the relationship between this structure and cognitive measures linked to interhemispheric functioning. Participants with autism displayed reductions in total corpus callosum volume and in several of its subdivisions. Relationships were also observed between volumetric alterations and performance on several cognitive tests including the Tower of Hanoi test. These findings provide further evidence for anatomical alterations in the corpus callosum in autism, but warrant additional studies examining the relationship of this structure and specific measures of interhemispheric connectivity.

Emotion recognition was investigated in typically developing individuals and individuals with autism. Experiment 1 tested children (5-7 years, n = 37) with brief video displays of facial expressions that varied in subtlety. Children with autism performed worse than the control children. In Experiment 2, 3 age groups (8-12 years, n = 49; 13-17 years, n = 49; and adults n = 45) were tested on the same stimuli. Whereas the performance of control individuals was best in the adult group, the performance of individuals with autism was similar in all age groups. Results are discussed with respect to underlying cognitive processes that may be affecting the development of emotion recognition in individuals with autism.

Most reports of sensory symptoms in autism are second hand or observational, and there is little evidence of a neurological basis. Sixty individuals with high-functioning autism and 61 matched typical participants were administered a sensory questionnaire and neuropsychological tests of elementary and higher cortical sensory perception. Thirty-two percent of autism participants endorsed more sensory sensitivity items than any control participants. Both groups made few errors on elementary sensory perception items. Controls made few errors on higher cortical sensory perception items, but 30% of the autism participants made high numbers of errors. These findings support the common occurrence of sensory symptoms in high functioning autism based on first person report, and the presence of neurological abnormalities in higher cortical sensory perception.

Adaptive behavior in autism is highly variable and strongly related to prognosis. This study explored family history as a potential source of variability in adaptive behavior in autism. Participants included 77 individuals (mean age = 18) with average or better intellectual ability and autism. Parents completed the Family History Interview about the presence of broader autism phenotype symptoms and major psychiatric disorders in first degree relatives. Adaptive behavior was assessed via the Vineland Adaptive Behavior Scales (VABS). Based on family history variables, age, and intelligence quotient (IQ), 87% of participants were correctly classified as having impaired or average VABS scores. Family history of depression and shyness accounted for the most variance in VABS scores, and they had the greatest influence on VABS Socialization scores in particular. Possible underlying mechanisms include genetics, psychosocial factors, and social resources. This study provides initial evidence of the importance of family history to adaptive behavior in autism and has implications for genetics and treatment.

Data sharing in autism neuroimaging presents scientific, technical, and social obstacles. We outline the desiderata for a data-sharing scheme that combines imaging with other measures of phenotype and with genetics, defines requirements for comparability of derived data and recommendations for raw data, outlines a core protocol including multispectral structural and diffusion-tensor imaging and optional extensions, provides for the collection of prospective, confound-free normative data, and extends sharing and collaborative development not only to data but to the analytical tools and methods applied to these data. A theme in these requirements is the need to preserve creative approaches and risk-taking within individual laboratories at the same time as common standards are provided for these laboratories to build on.

Previous studies have reported working memory deficits in autism, but this finding has been inconsistent. One possibility is that deficits in this domain may be present only when working memory load exceeds some limited capacity. High-functioning individuals with autism performed the CANTAB computerized test of spatial working memory. Individuals with autism made more errors than a matched group of typically developing controls on this task, and were less likely to consistently use a specific organized search strategy to complete the task. Overall, these results demonstrate reduced spatial working memory abilities in autism, and extend previous findings by demonstrating that these deficits are significant when tasks impose heavier demands on working memory.

This study examined the effect of exemplar typicality on reaction time and accuracy of categorization. High-functioning children (age 9-12), adolescents (age 13-16), and adults with autism (age 17-48) and matched controls were tested in a category verification procedure. All groups showed improved processing throughout the lifespan for typical and somewhat typical category exemplars. However, individuals with autism responded more slowly than matched controls to atypical exemplars at all ages. The results are discussed in terms of potential differences in the type of processing that may be required for categorizing typical and atypical category exemplars. Parallels are also drawn to the results of previous studies on face processing in individuals with autism.

We evaluated the predictive accuracy of short forms of the Wechsler intelligence scales for individuals with high functioning autism. Several short forms were derived from participants who had received the full procedure. Stepwise multiple regression analyses were performed to determine the strength of association between the subtests included in the short form and IQ scores based upon the full test. These analyses were performed for all participants, and also for autism participants with atypical subtest profiles. In all analyses the percentages of explained variance were typically in the 0.8-0.9 range. It was concluded that short forms may be used with good predictive accuracy in individuals with high functioning autism, even when the subtest profile is atypical.

Attention processes in 103 children and adults with high functioning autism were compared with a matched control group using a battery of attention measures. Differences were found only on tasks which placed demands on cognitive flexibility or psychomotor speed, suggesting that purported attention deficits in autism may actually be primary deficits in complex decision making or psychomotor abilities. (Contains references.) (Author/DB)

thinking is generally highly correlated with problem-solving ability which is predictive of better adaptive functioning. Measures of conceptual reasoning, an ecologically-valid laboratory measure of problem-solving, and a report measure of adaptive functioning in the natural environment, were administered to children and adults with and without autism. The individuals with autism had weaker conceptual reasoning ability than individuals with typical development of similar age and cognitive ability. For the autism group, their flexible thinking scores were significantly correlated with laboratory measures of strategy formation and rule shifting and with reported overall adaptive behavior but not socialization scores. Therefore, in autism, flexibility of thought is potentially more important for adaptive functioning in the natural environment than conceptual reasoning or problem-solving. Keywords Autism * Conceptual reasoning * Problem solving * Adaptive behavior * Cognitive, Introduction An important goal of treatment in autism is to help the individual successfully function as independently as possible. This notion is captured by the construct of 'adaptive behavior ability,' [...]

This paper summarizes results of research on functional and structural abnormalities of the brain in autism. The current concept of causation is seen to involve multiple biologic levels. A consistent profile of brain function and dysfunction across methods has been found and specific neuropathologic findings have been found; but some research paradoxes still exist. (DB)