Tracing Autism’s Hidden Origins: Integrating EHR, AI Care Journeys, Exposomics, Mini-Brain Assembloids, and RNA Base Modifications to Reveal Convergent Pathways

Document Type

Conference Proceeding

Publication Date

5-2026

Publication Title

Physiology

Abstract

Monogenic forms of Autism Spectrum Disorder (ASD) have provided researchers with a plethora of biological pathways involved in neurodevelopmental alterations. However, our current knowledge of ASD causality can only explain around 20-30% of ASD cases, leaving a large need for expanded tools in identifying ASD risks. Over the past few years, Corewell Health has developed a workflow of patient-centric, lab-based, and data-driven approaches to identify factors that alter neurodevelopment and may be associated with ASD. We curated a list of 1,527 ASD-linked genes using ClinVar, SFARI, Open Targets Platform, CZI CellxGene single cell atlas, and CTDbase gene-toxicology associations to resolve a clustered overlap with other neurological conditions (intellectual disability, epilepsy, schizophrenia, and ADHD), enriched neurological cell types (brainstem motor neuron, L4 intratelencephalic projecting glutamatergic neuron, lamp5 GABAergic cortical interneuron), developmental timepoints (9 weeks post conception and 1 year of age), and multiple environmental factors modulating oxidative stress and inflammation. Utilizing the Corewell Health electronic health records, we have identified 932 duos where pregnancy complications can be linked to birth outcomes and later ASD diagnosis. Enriched conditions relative to national averages of all pregnancies include probable sepsis (68 cases, ~7x higher than expected), transient tachypnea (55 cases, ~3–5x higher), and neonatal hypoglycemia (57 cases, ~2–3x higher). Utilizing an AI-generated synthetic cohort of 50,000 pregnancy complications to capture heterogeneous correlations to child and maternal outcomes, we identify sepsis, preeclampsia, and gestational diabetes mechanisms in ASD development. A cohort of 26 pregnancy blood PAXgene direct Nanopore-based transcriptomes enriched for gestational diabetes and preeclampsia show unique events of autoimmunity and inflammation that overlap multiple of our biomarkers for ASD. Using iPSC-based mini-brains and blood-brain barrier multiregion brain assembloids, we further identified a convergent mechanism involving environmental modulators that overlap with peroxynitrite-stimulated oxidative stress and RNA base modifications in multiple ASD-associated genes. This work suggests a complex genetic by environmental interaction that converges into shared ASD outcomes from multiple pregnancy and early life events, such as genetic variants, heavy metal exposure, infections, and hypoxia.

Volume

41

Issue

Suppl 1

DOI

10.1152/physiol.2026.41.S1.23009

ISSN

1548-9221

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