De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L, which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes (G3BP1, G36P2, and UBAP2L) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRlNI, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

Automated summary

This study reports a newly identified neurodevelopmental disorder and suggests the importance of stress granules (SGs) in its pathology. By studying mice and analyzing data from a large number of patients, the researchers found that genetic variants in genes related to SGs were associated with the disorder. These findings provide significant insights into the underlying mechanisms of neurodevelopmental disorders.