Method

De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes

    • 1Gladstone Institute of Data Science and Biotechnology, San Francisco, California 94158, USA;
    • 2Department of Epidemiology and Biostatistics, University of California San Francisco, California 94158, USA;
    • 3Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA;
    • 4Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA;
    • 5Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California 94158, USA;
    • 6Bakar Computational Health Sciences Institute, University of California, San Francisco, California 94143, USA;
    • 7Chan Zuckerberg Biohub, San Francisco, California 94158, USA
Published July 8, 2026. https://doi.org/10.1101/gr.280394.124
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cover of Genome Research Vol 36 Issue 8
Current Issue:
August 2026, Vol. 36, No. 8
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Abstract

Three-dimensional genome organization plays a critical role in gene regulation, and disruptions can lead to developmental disorders by altering the contact between genes and their distal regulatory elements. Structural variants (SVs) can disturb local genome organization, such as the merging of topologically associating domains upon boundary deletion. Testing large numbers of SVs experimentally for their effects on chromatin structure and gene expression is time and cost prohibitive. To address this, we propose a computational approach to predict SV impacts on genome folding, which can help prioritize causal hypotheses for functional testing. We develop a weighted scoring method that measures chromatin contact changes specifically affecting regions of interest, such as regulatory elements or promoters, and implement it in the SuPreMo-Akita software. With this tool, we rank hundreds of de novo SVs (dnSVs) from autism spectrum disorder (ASD) individuals and their unaffected siblings based on predicted disruptions to nearby neuronal regulatory interactions. This reveals that putative cis-regulatory element interactions (CREints) are more disrupted by dnSVs from ASD probands versus unaffected siblings. We prioritize candidate variants that disrupt ASD CREints and validate our top-ranked locus using isogenic excitatory neurons with and without the dnSV, confirming accurate predictions of disrupted chromatin contacts. This study suggests that disrupted genome folding is a potential genetic mechanism in a subset of ASD cases and provides a general strategy for prioritizing variants predicted to disrupt regulatory interactions across tissues.

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