Major autism study uncovers biologically distinct subtypes, paving the way for precision diagnosis and care

(Press-News.org) Researchers at Princeton University and the Simons Foundation have identified four clinically and biologically distinct subtypes of autism, marking a transformative step in understanding the condition’s genetic underpinnings and potential for personalized care.

Analyzing data from over 5,000 children in SPARK, an autism cohort study funded by the Simons Foundation, the researchers used a computational model to group individuals based on their combinations of traits. The team used a “person-centered” approach that considered a broad range of over 230 traits in each individual, from social interactions to repetitive behaviors to developmental milestones, rather than searching for genetic links to single traits.

This approach enabled the discovery of clinically relevant autism subtypes, which the researchers linked to distinct genetic profiles and developmental trajectories, offering new insights into the biology underlying autism. Their results were published July 9 in Nature Genetics.

“Understanding the genetics of autism is essential for revealing the biological mechanisms that contribute to the condition, enabling earlier and more accurate diagnosis, and guiding personalized care,” said senior study author Olga Troyanskaya, director of Princeton Precision Health, the Maduraperuma/Khot Professor of Computer Science and the Lewis-Sigler Institute for Integrative Genomics at Princeton, and deputy director for genomics at the Center for Computational Biology of the Simons Foundation’s Flatiron Institute.

The study defines four subtypes of autism — Social and Behavioral Challenges, Mixed ASD with Developmental Delay, Moderate Challenges, and Broadly Affected. Each subtype exhibits distinct developmental, medical, behavioral and psychiatric traits, and importantly, different patterns of genetic variation.

Individuals in the Social and Behavioral Challenges group show core autism traits, including social challenges and repetitive behaviors, but generally reach developmental milestones at a pace similar to children without autism.  They also often experience co-occurring conditions like ADHD, anxiety, depression or obsessive-compulsive disorder alongside autism. One of the larger groups, this constitutes around 37% of the participants in the study. The Mixed ASD with Developmental Delay group tends to reach developmental milestones, such as walking and talking, later than children without autism, but usually does not show signs of anxiety, depression or disruptive behaviors. “Mixed” refers to differences within this group with respect to repetitive behaviors and social challenges. This group represents approximately 19% of the participants. Individuals with Moderate Challenges show core autism-related behaviors, but less strongly than those in the other groups, and usually reach developmental milestones on a similar track to those without autism. They generally do not experience co-occurring psychiatric conditions. Roughly 34% of participants fall into this category. The Broadly Affected group faces more extreme and wide-ranging challenges, including developmental delays, social and communication difficulties, repetitive behaviors and co-occurring psychiatric conditions like anxiety, depression and mood dysregulation. This is the smallest group, accounting for around 10% of the participants. “These findings are powerful because the classes represent different clinical presentations and outcomes, and critically we were able to connect them to distinct underlying biology,” said Aviya Litman, a Ph.D. student at Princeton and co-lead author.

Distinct genetics behind the subtypes For decades, autism researchers and clinicians have been seeking robust definitions of autism subtypes to aid in diagnosis and care. Autism is known to be highly heritable, with many implicated genes.

“While genetic testing is already part of the standard of care for people diagnosed with autism, thus far, this testing reveals variants that explain the autism of only about 20% of patients,” said study co-author Jennifer Foss-Feig, a clinical psychologist at the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai and vice president and senior scientific officer at the Simons Foundation Autism Research Initiative (SFARI). This study takes an approach that differs from classic gene discovery efforts by identifying robust autism subtypes that are linked to distinct types of genetic mutations and affected biological pathways.

For example, children in the Broadly Affected group showed the highest proportion of damaging de novo mutations — those not inherited from either parent — while only the Mixed ASD with Developmental Delay group was more likely to carry rare inherited genetic variants. While children in both of these subtypes share some important traits like developmental delays and intellectual disability, these genetic differences suggest distinct mechanisms behind superficially similar clinical presentations.

“These findings point to specific hypotheses linking various pathways to different presentations of autism,” said Litman, referring to differences in biology between children with different autism subtypes.

Moreover, the researchers identified divergent biological processes affected in each subtype. “What we’re seeing is not just one biological story of autism, but multiple distinct narratives,” said Natalie Sauerwald, associate research scientist at the Flatiron Institute and co-lead author. “This helps explain why past genetic studies often fell short — it was like trying to solve a jigsaw puzzle without realizing we were actually looking at multiple different puzzles mixed together. We couldn’t see the full picture, the genetic patterns, until we first separated individuals into subtypes.”

Autism biology unfolds on different timelines The team also found that autism subtypes differ in the timing of genetic disruptions’ effects on brain development. Genes switch on and off at specific times, guiding different stages of development. While much of the genetic impact of autism was thought to occur before birth, in the Social and Behavioral Challenges subtype — which typically has substantial social and psychiatric challenges, no developmental delays, and a later diagnosis — mutations were found in genes that become active later in childhood. This suggests that, for these children, the biological mechanisms of autism may emerge after birth, aligning with their later clinical presentation.

“By integrating genetic and clinical data at scale, we can now begin to map the trajectory of autism from biological mechanisms to clinical presentation,” said co-author Chandra Theesfeld, senior academic research manager at the Lewis-Sigler Institute and Princeton Precision Health.

A paradigm shift for autism research This study builds on more than a decade of autism genomics research led by Troyanskaya and collaborators, supported by the Simons Foundation and the U.S. National Institutes of Health, and most recently by Princeton Precision Health, an interdisciplinary initiative launched in 2022. It is enabled by the close integration of interdisciplinary expertise in genomics, clinical psychology, molecular biology, computer science and modeling, and computational biology — with experts from Princeton Precision Health, the Flatiron Institute and SFARI.

“It’s a whole new paradigm, to provide these groups as a starting point for investigating the genetics of autism,” said Theesfeld. Instead of searching for a biological explanation that encompasses all individuals with autism, researchers can now investigate the distinct genetic and biological processes driving each subtype.

This shift could reshape both autism research and clinical care — helping clinicians anticipate different trajectories in diagnosis, development and treatment. “The ability to define biologically meaningful autism subtypes is foundational to realizing the vision of precision medicine for neurodevelopmental conditions,” said Sauerwald.

While the current work defines four subtypes, “this doesn’t mean there are only four classes,” said Litman. “It means we now have a data-driven framework that shows there are at least four — and that they are meaningful in both the clinic and the genome.”

Looking ahead For families navigating autism, knowing which subtype of autism their child has can offer new clarity, tailored care, support and community. “Understanding genetic causes for more individuals with autism could lead to more targeted developmental monitoring, precision treatment, and tailored support and accommodations at school or work,” said Foss-Feig. “It could tell families, when their children with autism are still young, something more about what symptoms they might — or might not — experience, what to look out for over the course of a lifespan, which treatments to pursue, and how to plan for their future.”

Beyond its contributions to understanding autism subtypes and their underlying biology, the study offers a powerful framework for characterizing other complex, heterogeneous conditions and finding clinically relevant disease subtypes. As Theesfeld put it: “This opens the door to countless new scientific and clinical discoveries.”

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The paper, “Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs,” was published July 9 in Nature Genetics. In addition to Litman, Sauerwald, Foss-Feig, Theesfeld and Troyanskaya, co-authors include LeeAnne Green Snyder of the Simons Foundation, Christopher Y. Park and Yun Hao of the Flatiron Institute, and Ilan Dinstein of Ben Gurion University of the Negev, who contributed to the study during a sabbatical at the Simons Foundation. The research was supported in part by the U.S. National Institutes of Health and the Simons Foundation.

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