Four hidden types of autism revealed — and each tells a different genetic story

Good news! Uncovering the spectrum of autism.

"... 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.  ...

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. ...

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. 

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. ..."

From the abstract:

"Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory and clinical manifestations of the many forms of the condition.

Using a generative mixture modeling approach, we leverage broad phenotypic data from a large cohort with matched genetics to identify robust, clinically relevant classes of autism and their patterns of core, associated and co-occurring traits, which we further validate and replicate in an independent cohort.

We demonstrate that phenotypic and clinical outcomes correspond to genetic and molecular programs of common, de novo and inherited variation and further characterize distinct pathways disrupted by the sets of mutations in each class.

Remarkably, we discover that class-specific differences in the developmental timing of affected genes align with clinical outcome differences. These analyses demonstrate the phenotypic complexity of children with autism, identify genetic programs underlying their heterogeneity, and suggest specific biological dysregulation patterns and mechanistic hypotheses."

 

Four hidden types of autism revealed — and each tells a different genetic story | ScienceDaily "Scientists at Princeton and the Simons Foundation have identified four biologically distinct subtypes of autism, using data from over 5,000 children and a powerful new computational method. These subtypes—each with unique traits, developmental paths, and genetic signatures—promise to revolutionize how we understand, diagnose, and treat autism."

Major autism study uncovers biologically distinct subtypes, paving the way for precision diagnosis and care (original news release)

Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs (open access)

Fig. 1: Overview of study design and description of identified subclasses.