Genetic variants contribute significantly to the etiology of autism, and unlike single-nucleotide variants (SNVs), copy number variants (CNVs) are more difficult to detect from genetic sequencing datasets. The goal of this proposal is to significantly increase the yield of high-impact autism mutations by focusing on the discovery of both CNVs and SNVs in autism families from SPARK. Using established and novel computational pipelines, Evan Eichler and colleagues propose to work with the SPARK Consortium to generate a high-confidence set of potential pathogenic variants and then integrate these data into larger genetic variant databases to pinpoint pathogenic variants and novel genes associated with autism.

Abba Krieger and colleagues serve as statistical consultants to the Simons Foundation. In this role, they analyze autism data generated by SFARI. The current funding will be used to support statistical analyses on phenotypic and genotypic data from SPARK.

Stephanie Bielas plans to study an Asxl3 null mouse model to better understand the role that Asxl3-dependent deubiquitination activity plays in specifying neural progenitor cell transcriptional programs that regulate cortical neuronal fate.

In the current project, Nenad Sestan and Stephan Sanders plan to identify genomic variants and assess their effects on gene expression in single cells and brain tissue across human brain development. This will provide functional insight into neurobiological processes important for human brain development and function and which may be disrupted in neurodevelopmental and psychiatric disorders.

In this project, Karen Parker and her colleagues aim to determine whether the lower vasopressin levels that were observed in the cerebrospinal fluid of adult monkeys with naturally occurring social deficits are also found in “at-risk” infant monkeys. They also plan to test whether these infants exhibit poor social cognition abilities in multiple domains relevant to autism. The identification of biomarkers at an early developmental stage is a critical next step towards early pharmacological intervention in “at-risk” young monkeys, and ultimately, young children at risk for social challenges.

Mark Zylka plans to evaluate the extent to which molecular phenotypes worsen with age in Chd8^V986*/+ heterozygous mice, which harbor a loss-of-function autism-linked mutation. Results from this study are expected to highlight the importance of expanding the age range over which autism model mice are evaluated, with the ultimate aim of better understanding neuropathological changes in older individuals with ASD.

New technologies for efficiently manipulating genomes have expanded autism research to mammalian models beyond the mouse. Rats are highly social, cooperative animals which, unlike the mouse, live in large social colonies, making them an excellent model species for many of the social characteristics of autism. Peter Kind and colleagues at the Simons Initiative for the Developing Brain plan to generate an in-depth overview of the behavioral repertoire of rats carrying autism-causing genetic alterations. Providing the autism research community with a precise baseline characterization of behavioral phenotypes would help encourage scientific engagement with these models.

The Brief Observation of Symptoms of Autism (BOSA) provides a context of activities that can be presented by an adult (e.g., a parent, therapist) in 12–14-minutes to observe social communicative behavior and play/imagination, which can be placed within a framework of standardized codes. In the current project, Catherine Lord and So Hyun “Sophy” Kim aim to refine, standardize and disseminate the BOSA to clinical and research communities to help fill the gap left by not being able to carry out a valid Autism Diagnostic Observation Schedule (ADOS-2) while COVID-19 restrictions are in place.

Genetic variation in the SCN2A gene is a risk factor for ASD, but the functional consequences of the many different variants that have been identified to date remain unknown. In the current project, Alfred George plans to experimentally determine how genetic variants in SCN2A disrupt the function of the protein made from this gene. Results from the study will enable better categorization of variant pathogenicity and advance our knowledge about the molecular mechanisms through which SCN2A dysfunction can lead to ASD.

In the current project, Omer Bayraktar, in collaboration with Tomasz Nowakowski, plans to generate a spatio-temporal autism gene expression (STAGE) resource where intact human brain tissue will be surveyed using a new spatial transcriptomic methodology. The primary focus will be on validating the expression of autism risk genes in cortical subplate neurons across brain development.