Genomic and transcriptomic studies implicate fetal cerebral cortex transcriptional dysregulation in ASD, but the implicated regulatory elements, their target genes and their role in development remain unclear. Flora Vaccarino will use cortical organoids derived from individuals with ASD to investigate whether transcriptional dysregulation of specific cell types during early development represents a convergent pathophysiology in ASD.

DEAF1 is an ASD risk gene that is highly expressed in cortical and subcortical regions of the developing human brain. Despite its importance in ASD, the function of DEAF1 in human cortical development is largely unknown. In-Hyun Park plans to investigate the function of DEAF1 using human cortical and thalamic brain organoids.

Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of UBE3A. Mark Zylka plans to utilize CRISPR/Cas9 technology to activate the dormant but functional paternal Ube3a in a mouse model of Angelman syndrome and assess long-term effects on behavior. This preclinical gene therapeutic approach has the potential to advance a first-in-class treatment for an autism spectrum disorder.

Tbr1 is a high-confidence ASD risk gene that plays a crucial role in neocortical synaptic development. John Rubenstein plans to examine the molecular mechanisms by which Tbr1 regulates synaptogenesis in order to understand how alterations to Tbr1 contribute to ASD pathophysiology.