Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions

Interindividual variation in phenotypic penetrance and severity is found in many neurodevelopmental conditions, although the underlying mechanisms remain largely unresolved. Within individuals, homogeneous cell types (i.e., genetically identical and in similar environments) can differ in molecule abundance. Here, we investigate the hypothesis that neurodevelopmental conditions can drive increased variability in gene expression, not just differential gene expression. Leveraging independent single-cell and single-nucleus RNA sequencing datasets derived from human brain-relevant cell and tissue types, we identify a significant increase in gene expression variability driven by the autosomal aneuploidy trisomy 21 (T21) as well as autism-associated chromodomain helicase DNA binding protein 8 (CHD8) haploinsufficiency. Our analyses are consistent with a global and, in part, stochastic increase in variability, which is uncoupled from changes in transcript abundance. Highly variable genes tend to be cell-type specific with modest enrichment for repressive H3K27me3, while least variable genes are more likely to be constrained and associated with active histone marks. Our results indicate that human neurodevelopmental conditions can drive increased gene expression variability in brain cell types, with the potential to contribute to diverse phenotypic outcomes. These findings also provide a scaffold for understanding variability in disease, essential for deeper insights into genotype-phenotype relationships.