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ImportanceHeterogeneous mental health outcomes during the COVID-19 pandemic are recognized in the general population, but it has not been systematically assessed in youth with neurodevelopmental disorders (NDD), including autism spectrum (ASD).ObjectiveIdentify subgroups of youth with ASD/NDD based on the pandemic impact on symptoms and service changes, as well as predictors of outcomes.Design, Setting, and ParticipantsThis is a naturalistic observational study conducted across 14 North American and European clinical and/or research sites. Parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) adapted for Autism and Related Neurodevelopmental Conditions (AFAR) were cross-sectionally collected from April to October 2020. The sample included 1275, 5-21 year-old youth with ASD and/or NDD who were clinically well-characterized prior to the pandemic.Main Outcomes and MeasuresTo identify impact subgroups, hierarchical clustering analyzed eleven AFAR factors measuring pre- to pandemic changes in clinically relevant symptoms and service access. Random forest classification assessed the relative contribution in predicting subgroup membership of 20 features including socio-demographics, pre-pandemic service, and clinical severity along with indices of COVID-19 related experiences and environments empirically-derived from AFAR parent responses and global open sources.ResultsClustering analyses revealed four ASD/NDD impact subgroups. One subgroup - broad symptom worsening only (20% of the aggregate sample) - included youth with worsening symptoms that were above and beyond that of their ASD/NDD peers and with similar service disruptions as those in the aggregate average. The three other subgroups showed symptom changes similar to the aggregate average but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Pre-pandemic factors (e.g., number of services), pandemic environments and experiences (e.g., COVID-19 cases, related restrictions, COVID-19 Worries), and age emerged in unique combinations as distinct protective or risk factors for each subgroup. Together they highlighted the role of universal risk factors, such as risk perception, and the protective role of services before and during the pandemic, in middle childhood.Conclusions and RelevanceConcomitant assessment of changes in both symptoms and services access is critical to understand heterogeneous impact of the pandemic on ASD/NDD youth. It enabled the delineation of pathways to risk and resilience that include universal and ASD/NDD specific contributors.

The importance of extensive genetic testing of autism spectrum disorder (ASD) cases has been demonstrated repeatedly in research settings but such testing in clinical settings remains sporadic. Determining which individuals should be prioritized for expensive tests remains a challenge. Several guidelines have been released relating to clinical genetic evaluations and testing in the context of ASD and these guidelines may be informed by the results of genetic testing in large research cohorts. The current study summarizes findings from over 2,000 individuals with ASD who received genetic testing, including microarray and exome testing, through the Simons Simplex Consortium. A returnable genetic result is identified in 10% of cases, however, this yield increases based on four readily accessible phenotypes: female sex and the presence of intellectual disability, seizures or delayed walking. Combinations of these factors increase return rate further, with some combinations yielding a return rate over 50%. In conclusion, these four phenotypes provide a simple approach to prioritize genetic testing in a clinical setting and inform future clinical guidelines. Providing a systematic approach to decisions about who to test removes barriers for, and therefore decrease disparities in, reimbursable genetic testing for individuals diagnosed with ASD.

BackgroundSeveral recent initiatives have sought to better understand characteristic behaviors of rare genetic conditions associated with autism spectrum disorder (ASD). The onset of developmentally expected skills, such as walking and talking, serve as readily quantifiable aspects of the behavioral phenotype. The goals of this study were to describe attainment of major motor and language milestones in genetic conditions implicated in the etiology of ASD and other neurodevelopmental disorders and to compare those phenotypes to idiopathic ASD.MethodsParticipants ages 3 years and older were drawn from two Simons Foundation Autism Research Initiative-funded registries with consistent phenotyping protocols. Inclusion criteria consisted of a confirmed genetic diagnosis for one of 16 specific genetic conditions (Simons Searchlight), and absence of pathogenic genetic findings in idiopathic ASD controls (SPARK). Parent-reported age of acquisition of three motor and two language milestones was described and quantified as on-time or delayed relative to normative expectations.ResultsDelay was more common among participants with rare genetic conditions than idiopathic ASD for all milestones. Compared to the idiopathic ASD group, the median odds of delay among the genetic groups were 8.3 times (IQR 5.8-16.3) higher for sitting, 12.4 times (IQR 5.3-19.5) higher for crawling, 26.8 times (IQR 7.7-41.1) higher for walking, 2.7 times (IQR 1.7-5.5) higher for single words, and 5.7 times (IQR 2.8-18.3) higher for combined words.ConclusionDelays in major developmental milestones, particularly in motor skills, may be among the earliest clues that developmental processes may be differentially affected in specific genetically defined conditions versus a behaviorally defined disorder such as idiopathic ASD.

SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.