Patchy brain development may help explain autism's varied traits

by Agency for Science, Technology and Research (A*STAR), Singapore

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Autism spectrum disorder (ASD) affects every individual differently. Scientists have identified more than a thousand genes associated with ASD, yet no single gene accounts for most cases. This has left researchers with a longstanding question: How can such diverse genetic changes give rise to the same condition yet affect each person so differently?

A new study by researchers from A*STAR Genome Institute of Singapore (A*STAR GIS), in collaboration with A*STAR Bioinformatics Institute (A*STAR BII), offers a new perspective. Published in Nature Communications, the study suggests that ASD may arise not only from which genes are affected but also from where and how the changes unfold as the brain develops.

Recreating early brain development in the laboratory

To investigate this question, the researchers generated brain organoids from induced pluripotent stem cells donated by individuals with and without ASD. These three-dimensional cellular models recreate key stages of fetal brain development that cannot be directly studied in humans. They then combined single-cell gene activity mapping with advanced computational analysis to identify individual cell types, map their locations and track how they assemble during brain development.

A patchwork of developmental changes

Using these approaches, the researchers observed striking differences between brain organoids from donors with and without ASD. Organoids from donors without ASD formed the orderly layers typical of the developing cerebral cortex, the brain's outer layer. In organoids from donors with ASD, this layered structure often broke down in distinct patches, while nearby areas developed normally.

Importantly, the distribution and extent of these disorganized patches differed between individuals. These findings suggest that ASD does not arise through a single uniform developmental process, but through distinct spatial patterns of brain development, pointing to a new model for autism pathogenesis.

Clues to how these patches form

The researchers traced these structural changes back to radial glial cells, the neural stem cells that serve as both the architects and scaffolding of the developing brain. Normally, these cells stay closely connected while guiding newly born neurons into their proper positions. In the ASD organoids, these connections were disrupted. As a result, the supporting scaffold became disorganized, and neurons failed to arrange themselves into their normal layered structure.

These abnormalities persisted into later stages of development, suggesting that subtle changes in how neural stem cells interact early in development may have lasting consequences for how the brain's outer layer (cerebral cortex) is assembled.

A new way of thinking about autism

Much of ASD research has focused on defining the genes and biological pathways involved. This study suggests that knowing where and how these molecular changes are organized across the developing brain provides an important complementary perspective. "By looking at how brain cells assemble into tissues, we may better understand why autism presents so differently from one person to another," said Dr. Liu Jinyue, principal scientist at A*STAR GIS and co-corresponding author of the study. In the longer term, this framework could improve how ASD is classified and help identify new opportunities for intervention.

Paving the way for complex human disorders

The study brought together A*STAR GIS's expertise in spatial genomics and stem cell biology, and A*STAR BII's expertise in computational biology. These complementary strengths enabled the team to reconstruct early brain development at single-cell resolution and reveal biological patterns that would have remained hidden using any single approach alone.

"Understanding biology is not only about which cells are present, but also where they are and how they interact. By adding the spatial dimension and combining diverse expertise, we can study not just autism but also other complex human diseases in entirely new ways. This has exciting potential to advance precision health through more accurate disease classification and ultimately more targeted treatment approaches," said Dr. Wan Yue, executive director of A*STAR GIS.

Publication details

Li Lin et al, Spatial architecture of autism pathogenesis reveals mosaic structural disarray during early development, Nature Communications (2026). DOI: 10.1038/s41467-026-74320-5

Journal information: Nature Communications

Key medical concepts

Autism Spectrum DisorderCerebral Cortex

Clinical categories

NeurologyClinical geneticsChildren's health Provided by Agency for Science, Technology and Research (A*STAR), Singapore Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

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