Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent

CHARGE syndrome is a rare disorder characterized by a spectrum of defects affecting multiple tissues and behavioral difficulties such as autism, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety, and sensory deficits. Most CHARGE cases arise from de novo , loss-of-function mutations in a master transcriptional regulator, chromodomain-helicase-DNA-binding-protein-7 (CHD7). CHD7 regulates key neurodevelopmental factors and is required for neural processes including neuronal differentiation and neural crest cell migration, but how CHD7 affects neural circuit function to regulate behavior is unclear. To investigate the pathophysiology of behavioral symptoms in CHARGE, we established a mutant chd7 zebrafish line using CRISPR/Cas9 that recapitulates multiple CHARGE phenotypes. Using a panel of behavioral assays, we find that chd7 mutants have specific auditory and visually driven behavioral deficits that are independent of defects in sensory structures, implicating chd7 in the regulation of underlying brain circuits. Furthermore, by analyzing multiple chd7 alleles we show that the penetrance of morphological and behavioral phenotypes depends on the mutation location. These results provide novel insight into the heterogeneity of CHARGE syndrome and will inform future work to define mechanisms of CHD7-dependent neurobehavioral symptoms. Summary statement Mutation location within chd7 affects the expression of CHARGE Syndrome-related morphological and behavioral phenotypes in a larval zebrafish CHARGE model.