Rare Copy Number Variants Reveal Critical Cell Types and Periods of Brain Development in Neurodevelopmental Disorders

Background

Multiple copy number variations (CNVs) in the human genome are associated with neurodevelopmental disorders (NDDs). Their markedly larger effect sizes and penetrance than common risk variants make them invaluable for investigating the etiology of NDDs.

Methods

We integrated >1 million single-cell transcriptomes from multiple datasets, capturing major brain regions and the entire timeline of human brain development. We performed expression-weighted cell-type enrichment analysis of genes contained in 127 CNVs associated with NDDs to identify human brain cell types, brain regions, and periods of development most susceptible to variations in gene dosage.

Results

We identified 3 groups of CNVs differentially enriched in developing cell types. Two groups of CNVs were preferentially expressed during early fetal brain development. While group A could be defined as developing neuron CNVs, group B was precursor CNVs, which were highly enriched in radial glia. Group A CNVs were associated with synaptic signaling, suggesting that synaptic dysfunction observed in NDDs may originate very early during fetal brain development. Group B CNVs were related to cell cycle and suggest dysfunction in proliferation and differentiation of precursor cells. Postnatally, expression of groups A and B genes was enriched in intratelencephalic neurons that integrate cortical information.

Conclusions

Overall, we showed that although NDDs are only diagnosed during childhood or adolescence, the actual effect of genetic mutations on embryonic progenitor cells or early neurons may be strongest during fetal brain development, which could program the cascade for subsequent developmental changes and, together with further postnatal dysfunction, impair brain function.