SUMMARY Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single nucleotide variants to autism spectrum disorders (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. Through the application of a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR=1.6; 95%CI=1.0-2.7; p=0.03), are more common in female probands (p=0.02), are enriched among genes encoding FMRP targets (p=6×10−9), and arise predominantly on the paternal chromosome (p<0.001). Based on mutation rates in probands versus unaffected siblings, de novo frameshift indels contribute to risk in approximately 3.0% of individuals with ASD. Finally, through observing clustering of mutations in unrelated probands, we report two novel ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

Background Because of its centrality in the conceptualization of intellectual disability, reliable and valid measurement of adaptive behaviour is important to both research and clinical practice. The manual of the Vineland Adaptive Behavior Scales, recently released in its third edition, provides limited reliability information obtained from a sample composed primarily of typically developing individuals. The goal of this study was to evaluate the concordance of the Vineland-3 with the Vineland-II in a sample more similar in ability level to those in which the Vineland is commonly used. Methods Both editions of the Vineland Interviews were conducted with a convenience sample of 106 parents/caregivers of individuals with neurodevelopmental disability, participating at two neurodevelopmental disorder research clinics. Administrations were up to 7 days apart, but most (90%) were simultaneous. The concordance correlation coefficient (CCC) (95% confidence interval) and mean differences (95% confidence interval) were calculated for domain standard scores and subdomain v-scale scores. Results Domain-level CCC ranged from 0.78 [0.70, 0.84] (Communication) to 0.86 [0.76, 0.92] (Motor). Subdomain CCC ranged from 0.71 [0.62, 0.78] (Receptive Language) to 0.91 [0.85, 0.95] (Fine Motor). Vineland-3 scores were lower than Vineland-II scores; 77% of participants had lower Adaptive Behavior Composite scores on the Vineland-3 than on the Vineland-II. For the subdomains, the magnitude of this difference depended upon the level of adaptive behaviour. For Communication, the domain with the lowest CCC, the mean difference ranged from À13.70 [À8.03, À19.35] for a Vineland-II score or 85 to a difference of À19.18 [À12.28, À26.87] for a Vineland-II score of 40.

Background: Restricted and repetitive behaviors (RRBs) are core features of autism. Factor-analytic studies composed primarily of children have provided evidence for two domains of RRBs: Repetitive Sensory Motor (RSM) and Insistence on Sameness (IS) behaviors. The present study explores the validity of the Autism Diagnostic Interview-Revised (ADI-R) and the Repetitive Behavior Scale-Revised (RBS-R) for assessing these RRB subtypes in autistic adolescents and adults. Methods: The sample included 293 participants (M age = 19.89 years, SD age = 4.88 years) whose RRBs were assessed via ADI-R, RBS-R Caregiver Report or RBS-R Self-Report. Confirmatory factor analysis (CFA) was conducted to assess the validity of the two-factor structure for each instrument. Cronbach's alpha was computed to assess subscale reliability. Correlations were examined between instrument subscales and nonverbal intelligence quotient (NVIQ) and age. Results: Exploratory correlations were modest and provided weak evidence in favor of the utility of a CFA for the ADI-R. The RBS-R Caregiver and Self-Report CFA and internal consistencies supported the two-factor RSM and IS model tested. Consistent with previous literature, NVIQ was negatively correlated with the RBS-R Caregiver RSM subscale, but not meaningfully associated with IS. Neither RBS-R Self-Report subscale was meaningfully correlated with NVIQ. Across instruments, RSM subscales were correlated, but associations between IS were minimal. Conclusions: The present study provides initial support for the use of the RBS-R Caregiver and Self-Report to measure dimensions of RSM and IS behaviors in autistic adolescents and adults. The present data did not support the use of the ADI-R to assess these RRB subtypes in older individuals. Conclusions must be interpreted cautiously in light of the present study's sample limitations. Additional research is needed to understand differences in caregiver-reported and self-reported RRBs. Further research on RRBs in autistic adolescents and adults, particularly in samples with more gender and racial/ethnic diversity, is critical to inform community understanding and knowledge of autism in adulthood.What was the purpose of this study?The purpose of this study was to determine if the ADI-R and RBS-R are appropriate to assess RRBs in autistic adults. Since RRBs are broad, we focused on how well these instruments measure two categories of RRBs: Repetitive Sensory Motor (RSM) and Insistence on Sameness (IS) behaviors. RSM includes behaviors such as hand flapping and lining up objects. IS includes behaviors such as negative responses to change and adherence to specific routines. Research supports the ADI-R and RBS-R for assessing these categories in children; however, little is known about their use in older samples. This study aimed to address this research gap.What did the researchers do?We used existing data from autistic adolescent and adults assessed using ADI-R, RBS-R Caregiver, or RBS-R Self-Report. We assessed the relationships between items on each instrume...

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