Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to Chd8 haploinsufficiency.

Loss-of-function mutations in the autism-associated CHD8 gene are highly penetrant for trait and behavioral abnormalities in children, but there is substantial clinical heterogeneity in the occurrence and extent of disruptions between individuals. Using a large genetic reference panel of mice, we recently showed that this heterogeneity is, in part, regulated by genetic background. Here, we hypothesize that genetic background may also influence early life experiences, further shaping individual susceptibility to neurodevelopmental disorders. To test this, systematic observations were conducted to track behaviors during the rearing of genetically diverse Collaborative Cross offspring raised by genetically identical dams. Biostatistical and machine-learning analyses of the data reveal robust strain-dependent differences in both pup and maternal behaviors that significantly predict sex-specific alterations in body and brain weights, as well as social, anxiety-like, and cognitive trait disruptions following weaning due to Chd8 haploinsufficiency. These results suggest that phenotypic variability in disease models arises from an interaction between inherited mutations and genetically influenced early-life environments. This work highlights the value of incorporating genetic diversity into model systems to better understand the origins of heterogeneity in neurodevelopmental disorders.