New Genetic Map Unlocks Clues to Autism and Rare Brain Disorder

Jerusalem, 7 January, 2026 (TPS-IL) -- An international team of scientists has identified hundreds of genes that are essential for early brain development, uncovering new insights into the biological roots of neurodevelopmental disorders, including autism, and describing a previously unknown genetic condition that disrupts brain growth, the Hebrew University of Jerusalem announced.

The study, published in the peer-reviewed journal Nature Neuroscience, used large-scale CRISPR gene-editing technology to systematically determine which genes are required as embryonic stem cells developed into brain cells.

Led by Prof. Sagiv Shifman of Hebrew University’s Institute of Life Sciences in collaboration with Prof. Binnaz Yalcin of INSERM in France, the team of Israeli, French and Japanese scientists set out to answer a fundamental question in neuroscience: which genes are necessary for building a healthy brain, and what happens when that process fails?

Using a genome-wide CRISPR knockout screen, the researchers individually disabled nearly 20,000 genes in embryonic stem cells as they transitioned into neural cells. This allowed the team to observe, step by step, which genes were indispensable for normal neural differentiation. In simple terms, neural differentiation is how a generic early cell learns to become a brain or nerve cell. Through this approach, the scientists identified 331 genes that are essential for generating neurons, many of which had not previously been linked to brain development.

While the findings span a wide range of neurodevelopmental conditions, the implications for autism stood out in both the data and in The Press Service of Israel’s interview with Shifman. The study’s results suggest that not all neurodevelopmental disorders arise from the same types of genetic disruptions, and that timing during brain development plays a critical role.

Autism Risk Genes Emerge

“The study delivers a genome-wide, stage-resolved essentiality map of neural differentiation,” Shifman told TPS-IL. “By knocking out about 20,000 genes during the transition from embryonic stem cells to neural lineages, we identified 331 genes required for neuronal generation and showed how this map can both interpret human genetic risk and help discover new neurodevelopmental disease genes.”

According to the study, genes that are broadly essential for basic cellular survival tend to be associated with more global developmental delay. In contrast, genes that are especially critical at specific stages of nerve cell formation show a stronger association with autism. This distinction helps explain why autism often presents differently from other neurodevelopmental disorders, even when symptoms overlap.

“It supports a timing-based view of autism risk,” Shifman told TPS-IL. “Autism-associated genes are enriched among those that are particularly critical at specific steps of nerve cell formation, as opposed to those needed broadly for basic cellular viability. This suggests that autism genes are involved in early developmental processes required for generating neural progenitors and neurons.”

The dataset includes both known and previously unrecognized autism-related genes. While roughly 100 of the 331 essential genes had already been implicated in neurodevelopmental disorders, the majority represent new candidates for further study. “Only a minority of the essential genes we identified are currently implicated in neurodevelopmental disorders,” Shifman told TPS-IL. The findings significantly expand the pool of genes researchers can investigate.

New Brain Disorder Identified

Beyond autism, the study also describes a new neurodevelopmental disorder linked to mutations in the gene PEDS1. This gene is required for the production of plasmalogens, specialized membrane lipids that are abundant in myelin, the insulating layer around nerve fibers. In the CRISPR screen, PEDS1 emerged as crucial for nerve cell formation, with its loss leading to reduced brain size.

Genetic analyses of two unrelated families revealed rare PEDS1 mutations in children with severe developmental delay and abnormally small brains. Follow-up experiments confirmed that inactivating PEDS1 disrupts normal brain development, including the generation and migration of neurons, providing a clear mechanistic explanation for the clinical features observed.

In addition to identifying disease genes, the research sheds light on inheritance patterns. The team found that genes involved in regulating transcription and chromatin are more often linked to dominant disorders, where a mutation in a single gene copy is sufficient to cause disease. Metabolic genes, such as PEDS1, are more commonly associated with recessive disorders that require mutations in both copies of the gene. This relationship could help clinicians prioritize candidate genes when interpreting genetic test results.

The researchers have also made their findings widely accessible by launching an open online database that includes the full results of the CRISPR screen. Shifman credited PhD student Alana Amelan with driving the initiative. “We wanted our findings to serve the entire scientific community,” he explained.

Looking ahead, Shifman said the essentiality map will serve as a platform for future discoveries. “The natural next step is to use the essentiality map as a discovery platform,” he told TPS-IL, adding that his lab is now focusing on the mechanisms of specific autism genes, sex differences in diagnosis, and the biological basis of autism’s wide clinical diversity.