The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multicenter research study that aims to develop reliable and objective measurements of social function and communication in people with autism.
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.
Alfred George will employ an automated electrophysiology system to elucidate the functional consequences of a large set of SCN2A variants of unknown clinical significance associated with neurodevelopmental disorders, including autism and epilepsy.
Many individuals with ASD have mutations in chromatin modifiers and transcription factors. Neville Sanjana’s team aims to understand how mutations in these genes and in nearby noncoding regions alter chromatin structure and transcriptional regulation, generating a large-scale integrated dataset. Such data is expected to help pinpoint which ASD risk genes will yield the biggest benefit when targeted with gene augmentation therapeutics.
Neuronal activity triggers the expression of new genes that play a critical role in aspects of neural development and cognitive function. Building on evidence suggesting links between a class of ASD susceptibility loci (i.e., subunits of the BAF chromatin remodeling complex) and this form of gene regulation, Michael Greenberg and colleagues seek to determine whether disruption in neuronal activity-responsive chromatin remodeling underlies the effects of these ASD mutations.
Michael Gandal’s project combines basic science and translational investigations to provide a comprehensive characterization of the spatiotemporal trajectory, functional significance and translational potential of glial cell activation in autism.
Joseph Gleeson proposes to measure gonadal mosaicism for the presence of ASD-causative mutations. He also plans to use this information to stratify males into those with baseline risk and those with high risk of fathering a child with ASD.
Analyzing when, how, and in which cell types autism spectrum disorder (ASD) pathology arises within the human brain will require a genetically tractable model system that can mimic human embryonic and fetal brain development. In the current project, Jürgen Knoblich’s team plans to combine 3-D tissue culture, CRISPR-based perturbations and single-cell RNA sequencing technology to study transcriptomic alterations in response to loss-of-function mutations in high-risk ASD genes. By characterizing perturbation-induced transcriptomic changes across dozens of cell types in the developing human cortex, they hope to uncover common and unique molecular pathways that bridge genetic mutations to ASD phenotypes.
Anna-Sophie Rommel and her colleagues established a prospective pregnancy cohort, Generation C, in New York City in the early weeks of the COVID-19 pandemic to investigate the impact of maternal SARS-CoV-2 infection. The supplemental funding from SFARI will help to build the infrastructure to retain participants for longitudinal follow-up research. This will help the researchers to investigate longer-term effects of maternal SARS-CoV-2 infection and inflammation on child neurodevelopment, including risk for ASD.
Maternal coronavirus disease 2019 (COVID-19) may result in immune activation that impacts fetal brain development with implications for child neurodevelopment. In the current project, Andrea Edlow and colleagues plan to develop a rich COVID-19 biorepository that includes maternal blood, stool and rectal samples, as well as placental biopsies and breast milk. They also plan to establish a registry that tracks families over time. These studies will serve as a foundation for future studies that aim to understand how maternal COVID-19 infection impacts fetal and early childhood brain development.