By Wendy Greenberg
Princeton University researchers have co-led and contributed to a breakthrough study uncovering autism subtypes, which could lead to better diagnosis and care. Working with the Simons Foundation, the Princeton researchers have identified four clinically and biologically distinct subtypes of autism, which, they say, marks a “transformative step in understanding the condition’s genetic underpinnings and potential for personalized care.”
This work could open the door for more precise diagnoses and personalized support, according to the Simons Foundation website (simonsfoundation.org). It also explains that autism is classified as a “spectrum” because each case is different. “Scientists have struggled to parse through the many ways autism can manifest, much less to link these varying observable traits (called phenotypes) to underlying genetics,” the Simons summary states.
This study defines four subtypes of autism that exhibit distinct traits and different patterns of genetic variation. The study is described on princeton.edu/news as analyzing data from more than 5,000 children in an autism research study funded by the Simons Foundation. The researchers used a computational model to group individuals based on their combinations of traits. The team called this 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.”
The Princeton website article, written by Molly Sharlach of the Office of Engineering Communications, explains that the “discovery of clinically relevant autism subtypes,” which the researchers linked to distinct genetic profiles and developmental trajectories, offers new insights.
The subtypes are: Social and Behavioral Challenges, in which individuals show social challenges and repetitive behaviors but generally reach developmental milestones at a pace similar to children without autism; Mixed Autism Spectrum Disorder (ASD) with Developmental Delay, in which individuals tend to reach developmental milestones later than children without autism but do not show signs of anxiety, depression, or disruptive behaviors; Moderate Challenges, in which individuals show core autism-related behaviors, but less strongly than those in the other groups; and Broadly Affected, in which individuals face more extreme and wide-ranging challenges. The study more specifically defines these groups.
Each subtype has distinct genetics behind it, the study shows. This study ‘s approach, notes the Princeton article, “differs from classic gene discovery efforts by identifying robust autism subtypes that are linked to distinct types of genetic mutations and affected biological pathways.” It finds that while children in different subtypes share some traits, there are genetic differences.
“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.
“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, who, like the others, are quoted in the article.
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.”
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 the result of the integration of interdisciplinary expertise in genomics, clinical psychology, molecular biology, computer science and modeling, and computational biology.
For families navigating autism, states the article, knowing which subtype of autism their child has can offer tailored care and support. “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 Jennifer Foss-Feig, 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.
“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,” Foss-Feig is quoted.
The results were published July 9 in the journal Nature Genetics in a paper entitled, “Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs.”
The study was co-led by Litman, Sauerwald, and Troyanskaya, who holds joint appointments at Princeton and the Flatiron Institute, along with Christopher Y. Park and Yun Hao of the Flatiron Institute; LeeAnne Green Snyder and Foss-Feig of the Simons Foundation; Chandra Theesfeld of Princeton; and Ilan Dinstein of Ben Gurion University in Israel.