Characterization of De Novo Promoter Variants in Autism Spectrum Disorder with Massively Parallel Reporter Assays.

Scientists studied genetic changes in parts of DNA that control how genes are turned on or off, comparing autistic children to their non-autistic siblings. They found some genetic changes that affect how genes work, but surprisingly, autistic children didn't have more harmful changes than their siblings. This suggests these particular genetic changes may not be a major cause of autism.

This study investigated whether rare genetic variants in promoter regions (DNA sequences that control gene expression) contribute to autism spectrum disorder. Researchers analyzed 3,600 de novo mutations in promoter regions from autistic individuals and neurotypical siblings using massively parallel reporter assays in neural progenitor cells. They identified 165 functionally significant variants that affected gene transcription and were associated with active transcription markers and disrupted transcription factor binding sites. However, contrary to their hypothesis, they found no differences in functional impact between variants from autistic probands versus neurotypical controls, suggesting that rare promoter variants may not be a major contributing factor to ASD through the mechanisms tested.

Results suggest that rare de novo promoter variants may not be major contributors to autism risk through transcriptional disruption mechanisms. This informs genetic counseling and research priorities, indicating other genetic mechanisms may be more important for understanding autism causation.

Study limited to promoter regions only, used single cell type (neural progenitor cells), and did not find expected differences between cases and controls. Sample size details not provided, and functional assays may not capture all relevant biological contexts.

Autism spectrum disorder (ASD) is a common, complex, and highly heritable condition with contributions from both common and rare genetic variations. While disruptive, rare variants in protein-coding regions clearly contribute to symptoms, the role of rare non-coding remains unclear. Variants in these regions, including promoters, can alter downstream RNA and protein quantity; however, the functional impacts of specific variants observed in ASD cohorts remain largely uncharacterized. Here, we analyzed 3600 de novo mutations in promoter regions previously identified by whole-genome sequencing of autistic probands and neurotypical siblings to test the hypothesis that mutations in cases have a greater functional impact than those in controls.

We leveraged massively parallel reporter assays (MPRAs) to detect transcriptional consequences of these variants in neural progenitor cells and identified 165 functionally high confidence de novo variants (HcDNVs). While these HcDNVs are enriched for markers of active transcription, disruption to transcription factor binding sites, and open chromatin, we did not identify differences in functional impact based on ASD diagnostic status.