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Autism

Aviya Litman, Olga Troyanskaya and Chandra Theesfeld
Princeton University researchers Aviya Litman, Olga Troyanskaya, and Chandra Theesfeld are among the co-authors of a major study on autism subtypes and their underlying genetics. Photo: Denise Applewhite, Princeton University.

With several family members exhibiting some autistic traits, and with a history of teaching autists in my working life, I read numerous articles about autism. Here is one that I found interesting that I would like to share.

Researchers have discovered four autism subtypes that are both clinically and biologically distinct. This research offers a better understanding of the genetic foundations of autism and could support more personalized approaches to diagnosis and care.

Data from more than 5 000 children was applied a computational model to group individuals by shared patterns of traits. Researchers 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. The study identifies four distinct autism subtypes: 1. Social and Behavioral Challenges, 2. Mixed ASD with Developmental Delay, 3. Moderate Challenges, and 4. Broadly Affected. Each group displays unique profiles in terms of development, medical conditions, behavioral traits, psychiatric symptoms, and genetic variation.

Subtype 1: 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. However, they often experience additional conditions such as: a. ADHD, b. anxiety, c. depression, or obsessive-compulsive behaviour. This is one of the more common subtypes, representing about 37% of the study population.

Subtype 2: The Mixed Autism Spectrum Disorder (ASD) with Developmental Delay group is marked by delayed developmental milestones like walking and talking. Most individuals in this category do not exhibit anxiety, depression, or disruptive behavior. Mixed reflects the variation in social difficulties and repetitive behaviors within the group. Approximately 19% of participants belong to this category.

Subtype 3: 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 = the simultaneous presence of two or more medical conditions in a patient. This group makes up roughly 34% of participants.

Subtype 4: The Broadly Affected group have the most severe and wide-ranging symptoms, including significant developmental delays, 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.

The findings are powerful because the classes represent different clinical outcomes, and connect to distinct underlying biology.

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.

Genetic testing is part of the standard of care for people diagnosed with autism, but this testing reveals variants that explain the autism of only about 20% of patients. In contrast, this study identifies autism subtypes that are linked to distinct types of genetic mutations and affected biological pathways.

People in the Broadly Affected group exhibit the highest rate of damaging de novo mutations = genetic changes that arise spontaneously and are not passed down from either parent. Those in the Mixed ASD with Developmental Delay group were more likely to possess rare inherited genetic variants. Although both subtypes share key features, 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.

Researchers identified divergent biological processes affected in each subtype. Autism is not just one biological story, but multiple distinct narratives. Past genetic studies often fell short. It was like someone trying to solve a jigsaw puzzle without realizing that researchers were looking at multiple different puzzles mixed together. They couldn’t see the full picture, until individuals were separated into subtypes.

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. Previously much of the genetic impact of autism was thought to occur before birth. However, 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.

“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. 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, targeted care, support, and community. 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.

Reference: “Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs” by Aviya Litman, Natalie Sauerwald, LeeAnne Green Snyder, Jennifer Foss-Feig, Christopher Y. Park, Yun Hao, Ilan Dinstein, Chandra L. Theesfeld and Olga G. Troyanskaya, 9 July 2025, Nature Genetics. DOI: 10.1038/s41588-025-02224-z

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Gustav Fechner (1801 – 1887)

Portrait of Gustav Theodor Fechner (1801-1887)

This weblog post is being published on Fechner day, 2024-10-22. It celebrates the day in 1850 when Gustav Fechner decided not to waste his life sleeping, and to make lasting contributions to psychophysics or, as some people call it, experimental psychology. People who want a basic understanding of his life may prefer to read a Wikipedia article about him.

There are two reasons why Gustav Fechner has impinged on my life.

First, one of my children is a grapheme-colour synesthete where letters and numerals are perceived as inherently colored. Synesthesia, more generally, involves perception where stimulation of one sensory/ cognitive pathway leads to an involuntary experiences in a second sensory/ cognitive pathway. Other examples include people experiencing colours/ tastes/ odors, when listening to music.

John Locke (1632 – 1704), in 1690 reported a blind man who said he experienced the colour scarlet when he heard the sound of a trumpet. There is disagreement as to whether this described an instance of synesthesia or was simply metaphoric.

There are two types of synesthesia. 1) projective: when a person sees colors, forms or shapes when stimulated. It is the most commonly experienced, and most widely understood version of synesthesia. 2. associative: when a person feels a very strong but involuntary connection between the stimulus and the sense that it triggers.

For example, in chromesthesia (sound to color), a projector may hear a trumpet, and see a red circle in space, while an associator might hear a trumpet, and think very strongly that it sounds red.

The first medical account came from German physician Georg Tobias Ludwig Sachs (1786 – 2014) in 1812. In 1876, Fechner sampled the general public to estimate the size of the population experiencing grapheme-colour synesthesia. A 2013 article in Scientific American puts the number of synesthetes at about 4% of the population.

I am also acquainted with Fechner in terms of three methodologies he developed for experimental psychology. These were developed to find out various thresholds for a population.

Method of limits. An ascending series of stimuli are presented, in which the intensity of a variable stimulus is increased by predetermined steps until it can be perceived on 50 per cent of presentations (for an absolute threshold determination) or until a difference between it and a standard stimulus can be determined.

Method of adjustment. A test person is given control of intensity levels of a stimulus and is instructed to adjust it to the level where it is barely discernible. An average is based on several trials.

Method of constant stimuli. Variable stimuli are presented in random order, with the objecting of finding the smallest intensity that can be detected involving absolute thresholds or the smallest difference from a standard stimulus that can be detected in the case of a difference threshold. Currently, correctly identifying 75 per cent of presentations for detection or discrimination is used to set limits.

What I find most interesting about Fechner is his nature, divided as it was between scientist and metaphysical philosopher. His career was an unsuccessful attempt to unite these sides.

On one side, Fechner was at heart a positivist, advocating observation and measurement in science. This encouraged an interest in phenomenology and verificationism in philosophy. On the other side, his interest in metaphysics demanded a comprehensive cosmology, unattainable through scientific investigation. As the Stanford Encyclopedia of Philosophy asks, in its article about him, but fails to answer: How could he be both a cautious and sober scientist and a daring and imaginative metaphysician?

It acknowledges that these two sides represent conflicting approaches, romanticism and empiricism. Of particular importance to him were the writings of Friedrich Wilhelm Joseph Schelling (1775–1854), Lorenz Oken (1779 – 1851) and Henrik Steffans (1773 – 1845) , where the emphasis was on a larger picture. However, since he was a student of physics and physiology at the University of Leipzig, he was influenced by his mentors, Alfred Wilhelm Volkmann (1801 – 1877) and Ernst Heinrich Weber (1795 – 1878), engaged in the experimental psychology of perception.

Positivist writing include a two volume work: Elemente der Psychophysik (1860) = Elements of Pyschophysics, parts of which were translated by Herbert Sidney Langfeld (1912) about the relationship between the psychic and physical. Because it stressed the dependence of the mental on its physical expression and embodiment, Fechner’s philosophy of mind has been categorized as materialism. Metaphysically, he is classified as a panpsychist, someone who believes the cosmos is psychic. For a modern, logical proof of this see this Wikipedia article which contains a summary of Thomas Negel’s (1937 – ) work on Panpsychism originally published in Moral Questions (1979). Fechner published his work on the subject in: Nanna oder über das Seelenleben der Pflanzen (1848) and Zend-Avesta oder über die Dinge des Himmels und des Jenseits (1851).

Fechner believed that metaphysics should follow, not lead, the empirical sciences. He believed these to be autonomous, with a foundation independent of philosophy.

Any attempt to understand Fechner must come to terms with both sides of his personality. Many studies of Fechner are one-sided, emphasizing one side of him at the expense of the other. Indeed, the view supported by many modern philosophers is that Fechner’s philosophy is incomprehensible without knowing about his life.