Distinct autism mutations converge on shared pathways during early brain development in organoid models.
Autism is linked to hundreds of different genes, yet many autistic people share similar features.
Now, researchers at the University of California, Los Angeles (UCLA) and Stanford University report that distinct autism-linked mutations begin to converge on common biological pathways during early brain development.
Autism genetics points to shared brain mechanisms
Turning long lists of autism-linked genes into clear biological explanations has proven difficult.
“Modern medicine relies on defining mechanisms that underlie disease susceptibility. Genetics provides a starting point for understanding these mechanisms,” said senior author Dr. Daniel Geschwind, Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology, and Psychiatry at UCLA.
Genetic studies have moved faster than the tools needed to understand how those genes shape the human brain as it develops.
Previous analyses of postmortem brain tissue from autistic individuals have pointed to changes in genes involved in neuron development, synapses, and gene control. However, these samples are taken years after the brain has formed—showing the end result, rather than how those changes arise.
Many autism-linked genes are most active during early fetal development, a period that cannot be studied directly in people.
The new study used human stem cell–based brain models grown in the lab to track how different autism-linked mutations affected brain development over time.
Modeling early brain development in autism using stem cells
The team generated small, three-dimensional brain models known as cortical organoids, which mimic early stages of human brain development. The study included stem cell lines from people with eight rare genetic forms of autism, from individuals with idiopathic autism with no single known genetic cause, and from neurotypical controls. Multiple cell lines were used for each group to reduce the risk that results reflected individual variation rather than disease-related effects.
Idiopathic autism
Autism in which no single genetic mutation or known cause has been identified, likely reflecting the combined effects of many small genetic risk factors.
The organoids were grown and analysed over ~100 days, covering early developmental stages and making it one of the largest longitudinal organoid studies yet focused on autism genetics. The researchers measured gene activity at several time points using RNA sequencing.
Early on, each genetic mutation produced its own pattern of changes, but as development progressed, these differences became less distinct. By later stages, gene activity across many of the mutations began to converge, with the strongest overlaps occurring at later stages of organoid development, suggesting that shared effects emerge as neurons mature.
“Think of it like different routes leading to similar destinations,” said Geschwind. “The mutations start by affecting different aspects of early brain development, but they end up impacting overlapping pathways.”
The shared pathways were linked to neuron maturation, synapse formation, and the control of gene activity. Further analysis pointed to a group of genes involved in organizing DNA and regulating which genes are switched on or off. These genes sit high in the regulatory chain, influencing many downstream processes previously linked to autism.
To test whether this network played an active role, the team reduced the activity of several key regulators using CRISPR-based methods in neural cells. This led to downstream changes similar to those seen in the autism models.
However, organoids from individuals with idiopathic autism showed less consistent changes, likely reflecting the complex and distributed genetic risk seen in most autism cases.
What converging pathways mean for autism research
Rather than acting through identical early defects, the findings suggest that diverse mutations may converge later on common regulatory systems that shape brain development.
“Our work extends previous findings suggesting that, despite the genetic complexity of autism, there are common biological changes that we can identify and track as they emerge during early brain development,” said Geschwind. “The hope is that by defining these shared mechanisms that may be able to eventually explain why, despite such genetic heterogeneity, patients share common behavioral features.”
However, the study does not link molecular changes to behavior. Organoids also lack long-range connections, environmental inputs, and later stages of development. The findings also apply mainly to rare, single-gene forms of autism, not the more common polygenic cases.
Future studies will likely build on this framework using single-cell and spatial methods to pinpoint which cell types are most affected.
“This work demonstrates how stem cell models can help us understand neurodevelopmental conditions during the developmental periods most relevant to disease origins,” said Geschwind.
Larger cohorts and closer integration with human brain data will be needed, with the plan that these approaches may help turn genetic complexity into clearer biological insight for autism research.