In one of the more comprehensive genetic explorations of autism so far, a team of Princeton University researchers pinned down four distinct subtypes of the disorder. Each of these subtypes boasts their own unique clinical features, genetic makeup, and developmental pathways.
The paper, published in Nature Genetics, could upend the way we diagnose (or even understand) autism, which should help push treatment options past a one-size-fits-all model to a more tailored approach.
The research team, which also included scientists from the Flatiron Institute and the Simons Foundation, pored over data from more than 5,000 autistic individuals drawn from the SPARK study. By pairing meticulous behavioral profiles with fresh genetic data, the team took advantage of advanced computational modeling algorithms to classify individuals into one of four phenotypic classes.
Four Autism Subtypes
These classes don’t just capture the core characteristics of autism. They also encompass common co-occurring conditions as well, such as ADHD, anxiety, and developmental delays.
- The largest group, Social and Behavioral Challenges, comprise about 37% of the study participants. These include individuals who experience notable social and behavioral challenges, elevated rates of ADHD and anxiety, but without significant developmental delays.
- The Mixed ASD with Developmental Delay class – making up 19% of the total – exhibit a complex pattern, including high rates of developmental delays, language impairments, and intellectual disabilities. However, these individuals have less pronounced behavioral issues.
- A third group, Moderate Challenges (34%), includes those with relatively mild symptoms across most categories.
- Finally, the smallest group, Broadly Affected (10%), includes those with severe challenges across nearly every category, including the highest levels of cognitive impairment, developmental delays, and psychiatric conditions.
Crucially, the researchers confirmed all four classes in a separate, independent autism cohort.
“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,” Princeton PhD student and co-lead author Aviya Litman said.
Genetic Signatures Crop Up
Beyond their behavioral differences, these subtypes also showed distinct genetic fingerprints. The researchers looked at both common genetic variants and rare mutations to get a better grasp of the biological traits of each group.
The Broadly Affected class stood out for carrying the highest burden of rare, high-impact “de novo” mutations, particularly in genes vital to brain development. Many researchers have already tied these genes to intellectual disabilities and severe developmental disorders.
Conversely, the Mixed ASD with Developmental Delay subtype showed a mix of de novo and inherited rare mutations, which hints at a more complicated genetic inheritance pattern. Mutations affecting genes active during prenatal brain development also appeared to be more common.
The Social/behavioral class, on the other hand, revealed influences from common genetic variants tied to psychiatric traits such as ADHD and depression. Mutations in this group tended to affect genes active after birth, particularly in brain cells involved in social and emotional processing.
It’s worth noting that none of the four classes showed a strong association with common genetic variants tied specifically to autism itself, which points to the intricate interactions between various genetic risk factors.
A Path Toward Tailored Autism Care?
These results offer compelling evidence that autism isn’t just a single condition. It’s a collection of distinct, biologically grounded subtypes. The study’s authors add this framework could help improve diagnostic accuracy and eventually guide more personalized interventions.
“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.
The study marks a major step toward a more nuanced understanding of autism, accounting for its robust diversity and roots in both genetics and development.
Further Reading
Latest Analysis Explores Global Autism Rates and Health Burden
Management of Autism in Clinical Settings
Siblings With Autism Share More of Father’s DNA, Not Mother’s
