Groundbreaking Study Identifies Four Biologically Distinct Autism Subtypes
Researchers from Princeton University and the Simons Foundation have discovered four autism subtypes that are both clinically and biologically distinct. This breakthrough offers a deeper understanding of the genetic foundations of autism and could support more personalized approaches to diagnosis and care. The findings provide new perspectives on the biological complexity of autism and were published in the journal Nature Genetics.
Using data from more than 5,000 children in the SPARK autism cohort study, which is funded by the Simons Foundation, the research team applied a computational model to group individuals by shared patterns of traits. Rather than focusing on single genetic links, they adopted a “person-centered” strategy that evaluated more than 230 traits per participant, including social behavior, repetitive actions, and developmental progress.
This method led to the identification of meaningful autism subtypes, each tied to unique genetic markers and developmental patterns.
“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 identifies four distinct autism subtypes: Social and Behavioral Challenges, Mixed ASD with Developmental Delay, Moderate Challenges, and Broadly Affected. Each group displays unique profiles in terms of development, medical conditions, behavioral traits, psychiatric symptoms, and genetic variation.
The Social and Behavioral Challenges group is characterized by core autism features, such as difficulties with social interaction and repetitive behaviors, but these individuals typically meet developmental milestones at a similar rate as their neurotypical peers. They frequently experience additional conditions such as ADHD, anxiety, depression, or obsessive-compulsive disorder. This is one of the more common subtypes, representing about 37% of the study population.
The Mixed ASD with Developmental Delay group is marked by delayed developmental milestones like walking and talking, yet most individuals in this category do not exhibit anxiety, depression, or disruptive behavior. The term “Mixed” reflects the variation in social difficulties and repetitive behaviors within the group. Approximately 19% of participants belong to this category.
Those in the Moderate Challenges group display autism-related behaviors, but these traits tend to be less pronounced than in the other subtypes. Their developmental milestones generally align with typical patterns, and they rarely show psychiatric comorbidities. This group makes up roughly 34% of the cohort.
The Broadly Affected group experiences the most severe and wide-ranging symptoms, including significant delays in development, difficulties with social communication, repetitive behaviors, and coexisting psychiatric conditions such as anxiety, depression, and mood instability. This is the smallest group, comprising about 10% of 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.
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, th is 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 instance, children classified under the Broadly Affected group exhibited the highest rate of damaging de novo mutations (genetic changes that arise spontaneously and are not passed down from either parent). In contrast, only those in the Mixed ASD with Developmental Delay group were more likely to possess rare inherited genetic variants. Although both subtypes share key features, such as developmental delays and intellectual disability, these genetic distinctions point to separate biological mechanisms underlying what may appear to be similar clinical traits.
“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.”
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.
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.”
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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