SUMMARY Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Highlights d 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR % 0.1) d Most are expressed and enriched early in excitatory and inhibitory neuronal lineages d Most affect synapses or regulate other genes; how these roles dovetail is unknown d Some ASD genes alter early development broadly, others appear more specific to ASD

The Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000) is widely accepted as a "gold standard" diagnostic instrument, but it is of restricted utility with very young children. The purpose of the current project was to modify the ADOS for use in children under 30 months of age. A modified ADOS, the ADOS Toddler Module (or Module T), was used in 360 evaluations. Participants included 182 children with best estimate diagnoses of ASD, non-spectrum developmental delay or typical development. A final set of protocol and algorithm items was selected based on their ability to discriminate the diagnostic groups. The traditional algorithm "cutoffs" approach yielded high sensitivity and specificity, and a new range of concern approach was proposed.Keywords autism spectrum disorders; diagnosis; ADOS; infants; toddlers Almost ten years ago, the standardization of a revised Autism Diagnostic Observation Schedule (ADOS), a semi-structured assessment for the diagnosis of autism spectrum disorders (ASD) (Lord, Rutter, DiLavore & Risi, 1999) was described. The ADOS has gradually become an integral part of many research and clinical protocols of children suspected of having an autism spectrum disorder (ASD). Due to the growing understanding of symptoms in the first two years of life and the desire of researchers and clinicians to have standardized instruments for use with infants and young toddlers, there is a need for diagnostic tools that are appropriate for very young children. This paper presents a new Toddler Module of the ADOS. The Toddler Module retains the original spirit and many of the original tasks of the ADOS, but is intended for use in children under 30 months of age who have nonverbal mental ages of at least 12 months. The scope of this report is to provide a summary of the new measure, the procedures used to develop it, a description of the standardization sample and relevant psychometrics.In introducing this new module, it is valuable to review the structure of the previously published ADOS. The ADOS evaluates social interaction, communication and play through a series of planned "presses" (Lord et al., 1989) in the context of a naturalistic social interaction. Some of the presses are intended to offer a high level of structure for the participant, while others are intended to provide less structure. All presses, however, afford contexts for both initiations and responses, which are then coded in a standardized manner. An algorithm, which sums the scores of particular items from the measure, yields a classification indicative of autism, ASD or nonspectrum conditions. This classification can then be used by a clinician or researcher as one part of a comprehensive diagnostic process.The first ADOS was introduced in the late 1980s and was intended for children who had a spoken language age equivalent of at least 36 months. A revision was published in 2000 that reflected the need for the measure to be applicable to a wider range of chronological and developmental ages. The 2000 version provided f...

The present study explored the relationship between nonverbal IQ and restricted and repetitive behaviors (RRBs) in 830 children with Autism Spectrum Disorders. The role of chronological age as a moderator of this relationship was also investigated. For many behaviors, there was a significant interaction between nonverbal IQ and chronological age, such that nonverbal IQ (NVIQ) was more strongly related to the prevalence of RRBs in older children. For the majority of such behaviors (e.g. repetitive use of objects, hand and finger mannerisms), RRB prevalence was negatively associated with NVIQ. However, the prevalence of certain behaviors (e.g. circumscribed interests) showed positive relationships with NVIQ, which provides some support for the idea of different classes of RRBs. For the severity of different RRBs, there were several significant effects for age and NVIQ, but few interactions.

Objective To examine differences in behavioral symptoms and cognitive functioning between males and females with autism spectrum disorder (ASD). Method We analyzed data from 2,418 probands with autism (304 females, 2,114 males) included in the Simons Simplex Collection. Sex differences were evaluated across measures of autism symptoms, cognitive and motor functioning, adaptive behavior, and associated behavior problems. Measurement bias was examined using latent variable models of symptoms. Unadjusted and propensity-adjusted analyses were computed to ensure sex differences were not due to unbalanced sampling. Moderator and mediator analyses evaluated whether sex differences were modified by clinical characteristics or driven by cognitive ability. Results Females with ASD had greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females. IQ reductions mediated greater social impairment and reduced adaptive behavior in females with ASD, but did not mediate reductions in restricted interests or increases in irritability. Conclusions A specific female ASD phenotype is emerging that cannot be accounted for by differential symptom measurement. The present data suggest that the relatively low proportion of high functioning females may reflect the effect of protective biological factors or may be due to under-identification. Additional carefully-accrued samples are needed to confirm the present pattern and to evaluate whether observed sex ratios in high functioning cases are reduced if female-specific indicators of restricted interests are included.