MECHANISMS OF MOTOR IMPAIRMENTS IN AUTISM SPECTRUM DISORDER

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition frequently accompanied by motor impairments, affecting up to 80% of autistic children. Notably, motor deficits often emerge before the core social and communication features of ASD, suggesting that early motor dysfunction may contribute to later social impairments. While many ASD risk genes have been studied in the context of synaptic functions in the central nervous system, the mechanisms underlying motor dysfunction remain poorly understood.
This study aims to establish a causal framework connecting ASD-associated genetic perturbations to early motor deficits by integrating in vivo genetics, quantitative behavioral analysis, and cell type-specific molecular profiling. We use zebrafish as a genetically and behaviorally tractable vertebrate model to systematically progress from gene perturbation to mechanism and functional rescue.
To enrich for genes most relevant to early motor output, we prioritized ASD risk genes based on developmental expression and functional relevance to motor systems. High-confidence ASD risk genes (SFARI score 1) were filtered using the Daniocell single-cell expression atlas. Genes were prioritized based on expression in neural and muscle cell populations and prior associations with motor or muscle phenotypes in the Human Phenotype Ontology and ZFIN databases.
Using these criteria, we identified 20 ASD risk genes implicated in neuronal differentiation, connectivity, chromatin regulation, RNA metabolism, and protein homeostasis. We generated and validated effective CRISPR-based perturbations for each gene in vivo. Ongoing work involves quantitative behavioral phenotyping to identify motility defects, metabolic measurements and subsequent cell-type–specific molecular analyses to define mechanisms underlying ASD-associated motor dysfunction.