SUMMARY Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of reenacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift towards GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.

Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology. We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD; the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism; and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonetheless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.

Background The ability to spontaneously attend to the social overtures and activities of others is essential for the development of social cognition and communication. This ability is critically impaired in toddlers with autism spectrum disorders (ASD); however, it is not clear if prodromal symptoms in this area are already present in the first year of life of those affected by the disorder. Methods To examine whether 6-month-old infants later diagnosed with ASD exhibit atypical spontaneous social monitoring skills, visual responses of 67 infants at high-risk (HR) and 50 at low-risk (LR) for ASD were studied using an eye-tracking task. Based on their clinical presentation in the 3rd year, infants were divided into those with ASD, those exhibiting atypical development (HR-ATYP), and those developing typically (HR-TYP, LR-TYP). Results Compared to the control groups, 6-month-old infants later diagnosed with ASD attended less to the social scene, and, when they did look at the scene, they spent less time monitoring the actress in general and her face in particular. Limited attention to the actress and her activities was not accompanied by enhanced attention to objects. Conclusions Prodromal symptoms of ASD at six months include a diminished ability to attend spontaneously to people and their activities. A limited attentional bias towards people early in development is likely to have a detrimental impact on the specialization of social brain networks and the emergence of social interaction patterns. Further investigation into its underlying mechanisms and role in psychopathology of ASD in the first year is warranted.

Background In typical development, the unfolding of social and communicative skills hinges upon the ability to allocate and sustain attention towards people, a skill present moments after birth. Deficits in social attention have been well documented in autism, though the underlying mechanisms are poorly understood. Methods In order to parse the factors that are responsible for limited social attention in toddlers with autism, we manipulated the context in which a person appeared in their visual field with regard to the presence of salient social (child-directed speech and eye contact) and nonsocial (distractor toys) cues for attention. Participants included 13- to 25-month-old toddlers with autism (AUT; n=54), developmental delay (DD; n=22), and typical development (TD; n=48). Their visual responses were recorded with an eye-tracker. Results In conditions devoid of eye contact and speech, the distribution of attention between key features of the social scene in toddlers with autism was comparable to that in DD and TD controls. However, when explicit dyadic cues were introduced, toddlers with autism showed decreased attention to the entire scene and, when they looked at the scene, they spent less time looking at the speaker’s face and monitoring her lip movements than the control groups. In toddlers with autism, decreased time spent exploring the entire scene was associated with increased symptom severity and lower nonverbal functioning; atypical language profiles were associated with decreased monitoring of the speaker’s face and her mouth. Conclusions While in certain contexts toddlers with autism attend to people and objects in a typical manner, they show decreased attentional response to dyadic cues for attention. Given that mechanisms supporting responsivity to dyadic cues are present shortly after birth and are highly consequential for development of social cognition and communication, these findings have important implications for the understanding of the underlying mechanisms of limited social monitoring and identifying pivotal targets for treatment.

Autism spectrum disorders (ASD) often go undetected in toddlers. The Modified Checklist for Autism in Toddlers (M-CHAT) was used to screen 3,793 children aged 16-30 months from lowand high-risk sources; screen positive cases were diagnostically evaluated. Re-screening was performed on 1,416 children aged 42-54 months. Time 1 Positive Predictive Value (PPV) was .36 for the initial screening and .74 for the screening plus follow-up telephone interview; values were similar for Time 2 PPV. When separating referral sources, PPV was low for the low-risk sample but acceptable with the follow-up telephone interview. Children with ASD from the low-risk and high-risk samples were highly similar. Results indicate that the M-CHAT continues to be a promising instrument for the early detection of ASD.