A quarterly publication of the Autism Research Institute
Summer 2025 | Number 3, Volume 39
A large-scale study by researchers in the United States and Israel has identified four distinct subgroups of children with autism spectrum disorder (ASD), a finding that could lead to better targeting of interventions and research.
Aviya Litman and colleagues analyzed data on more than 5,000 children with ASD, ranging from four to 18 years of age, who are enrolled in the SPARK study. The researchers used a computational model to group the children based on more than 230 factors including developmental milestones, cognitive and behavioral traits, family history, and co-occurring conditions. Using this “person-centered” approach, rather than examining single traits, they were able to group the children into four subtypes:
—Thirty-seven percent of children fell into a category designated as “Social and Behavioral Challenges.” These children had many co-occurring traits, including attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, depression, and obsessive-compulsive disorder, and tended to exhibit restricted or repetitive behaviors. In addition, they experienced difficulties in communication. However, they generally hit developmental milestones on the same schedule as neurotypical children.
—Nineteen percent of children fell into a category designated as “Mixed ASD with Developmental Delay.” Although these children hit many of their milestones later in development than neurotypical peers, they typically did not exhibit anxiety, depression, or disruptive behaviors.
—Thirty-four percent of children were categorized as the “Moderate Challenges” group. These children exhibited some but not all of the behaviors of the “Social and Behavioral Challenges” group, and exhibited these behaviors to a lesser degree. This group typically did not have developmental delays or co-occurring psychiatric conditions.
—Ten percent of children were categorized as “Broadly Affected.” This group experienced a wide range of challenges, including restricted and repetitive behaviors, difficulties with social communication, developmental delays, mood dysregulation, anxiety, and depression.
Once the researchers identified the four categories, they used additional data from the SPARK study to explore the genetic patterns seen in each subtype. Surprisingly, they found that each category had its own “biological signature.” For example, they say, children in the Broadly Affected group had the highest proportion of de novo mutations (those not inherited from either parent) linked to autism, while only the Mixed ASD with Developmental Delay group had an elevated likelihood of possessing rare inherited genetic variants.
“There was little to no overlap in the impacted pathways between the classes,” Litman says. “And what was even more interesting is that while the impacted pathways—things like neuronal action potentials or chromatin organization—were all previously implicated in autism, each one was largely associated with a different class.” The timing of gene activation also differed by subtype, with some impacted genes mostly active after birth and others mostly active in the prenatal period.
The researchers emphasize that their subtypes are not definitive but rather a starting point. Senior study author Olga Troyanskaya comments, “This doesn’t mean that there’s necessarily only four classes. I think what this demonstrates is that there are at least four classes. But having the four, which are clinically and biologically relevant, is significant.”
The researchers say that accurately identifying subgroups of individuals with ASD could point to new research avenues and aid clinicians in planning effective interventions. Study coauthor Natalie Sauerwald says, “A clinically grounded, data-driven subtyping of autism would really help kids get the support they need early on. If you know that a person’s subtype often co-occurs with ADHD or anxiety, for example, then caregivers can get support resources in place and maybe gain additional understanding of their experience and needs.”
“Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs,” Aviya Litman, Natalie Sauerwald, LeeAnne Green Snyder, Jennifer Foss-Feig, Christopher Y. Park, Yun Hao, Ilan Dinstein, Chandra L. Theesfeld, and Olga G. Troyanskaya, Nature Genetics, July 9, 2025 (free online). Address: Natalie Sauerwald, [email protected], or Olga G. Troyanskaya, [email protected].
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“New study reveals subclasses of autism by linking traits to genetics,” news release, Simons Foundation, July 9, 2025.
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“Major autism study uncovers biologically distinct subtypes, paving the way for precision diagnosis and care,” news release, Princeton University, Engineering School, July 9, 2025.
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“Four autism subtypes map onto distinct genes, traits,” Giorgia Guglielmi, The Transmitter, July 17, 2025.
