Some human individuals develop autism: Is it a genetic mystery?

April 21, 2025 – Genetic factors are thought to play a major role in the development of autism,  but for decades what they are has proven elusive. Now scientists are starting to uncover clues. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive, restricted, and inflexible patterns of behavior, interests, and activities, as well as difficulties in social interaction and social communication. Sensory processing differences can impair functioning in different areas, such as developing social relationships or performing instrumental activities of daily living.

Until the 1970s, the prevailing belief in psychiatry was that autism was a consequence of bad parenting. Dr. Geschwind, a neuroscience and genetics professor at the University of California, Los Angeles (UCLA), says that this is now rightly recognised as being deeply damaging and wrong. It was not until 1977, when a couple of psychiatrists carried out a landmark study demonstrating that autism often runs in identical twins, that a more nuanced and accurate picture of autism’s origins began to emerge.

That 1977 study was the first time that a genetic component of autism had been identified. Research has since shown that when one identical twin is autistic, the likelihood that the other twin will be too can be more than 90%. Meanwhile, the chances of fraternal twins of the same sex each sharing a diagnosis of autism are around 34%. These levels are substantially higher than the typical rate of occurrence among the wider population, of around 2.8%.

It is now widely accepted that there is a strong genetic component to autism. But which genes are involved and how their expression is influenced by other factors are only just starting to be unravelled.

Tiny differences

Even after the twin study in 1977, it would take several more decades for the full subtleties of the interaction between autism and the human genome to become apparent. Between any two individuals, the amount of genetic variation is around 0.1%, meaning that approximately one letter or base pair out of every 1,000 in their DNA will be different. Sometimes these variations have no effect at all, sometimes they have a little effect, and sometimes they have a super strong effect.

Currently, super strong variations have been identified in up to 20% of all cases of autism, with a single mutation in a single gene being largely responsible for driving critical neurodevelopmental differences. The role of these single gene mutations and how they arise is one of the most heavily studied areas in autism research, because they often result in severe and life-limiting disability.

If you’re born with one of these major mutations, there’s a high likelihood you’ll end up with intellectual disability or motor delay [the ability to coordinate muscle groups] or epileptic encephalopathy. It has a major impact on their quality of life and their family in most cases.

So far scientists have identified at least 100 genes where these mutations can. Prof. Bourgeron at the Institute Pasteur in Paris made one of the first discoveries in March 2003 when he identified two gene mutations (i.e., mutations in the X-linked genes encoding neuroligins NLGN3 and NLGN4). Each impacted proteins involved in synaptogenesis, the process of forming connections between neurons in the brain. It was a major breakthrough, although it barely made a ripple in the media at the time,

But more discoveries were to come, including mutations in the Shank3 gene which are estimated to occur in less than 1% of people with autism. We now know that some of these mutations are known as de novo variants, which means that they occur through random chance in a developing embryo and aren’t present in the blood DNA of either the mother or father. Dr. Geschwind describes de novo variants as being akin to a “bolt of lightning”, that is both unexpected and rare.

However, in other cases, these mutations can have been passed on by one of the parents, even if both appear to be neurotypical, a more complex phenomenon which researchers have only begun to understand in the past decade.

“You might wonder, if an autistic child has inherited a rare gene mutation from one of their parents, why doesn’t the parent have autism too?” says Geschwind. “What seems to happen is that in the parent, it’s not sufficient to be causal, but in the child, that major gene mutation combines additively with other, less individually impactful gene variants to drive neurodevelopment differences,” he says.

Of course, there are also thought to be environmental factors involved in the development of autism – even among identical twins where one has been diagnosed, 10% of the time the other one will not be. According to the US National Institutes of Health (NIH), potential non-genetic causes of autism include prenatal exposure to air pollution and certain pesticides, extreme prematurity, and birth difficulties leading to oxygen deprivation in the baby’s brain, among other factors.

Early development

Today genetic research is leading progress into how neurodevelopment can lead to autism. It appears that many of these genes become functional during the formation of the cortex – the wrinkly outer layer of the brain responsible for many high-level functions, including memory, problem-solving and thinking.  This critical part of brain development occurs in the foetus as it is developing in the womb, and according to Geschwind, peaks somewhere between 12 and 24 weeks. One can think of these mutations as disrupting the normal patterns of development, knocking development off of its normal track so to speak and maybe onto another tributary, instead of the normal, neurotypical pattern of development.

Because they cause such severe disability, the information about these gene mutations has enabled parents to form support groups, for example the FamilieSCN2A Foundation which serves as a community for families of autistic children where the autism diagnosis has been linked to a genetic change in the SCN2A gene. Discussions have also been held regarding the idea of using such genetic information to influence future reproductive decisions.

A complex picture

In the past half century, genetics studies have shown that in the majority of autistic people, their neurodiversity arises through the additive effects of hundreds or even thousands of relatively common gene variants which they have inherited from both parents.These gene variants exist throughout the population of both neurotypical and neurodivergent people, and the individual contribution of any one of these genes to neurodevelopment is negligible. But in combination, they have a significant effect on the wiring of the brain. It seems not uncommon for one or both parents, who carry some of these gene variants, to display autistic traits such as a preference for order, difficulties in detecting emotions, and being hyperaware of patterns; but unlike their child, these traits do not manifest to such a significant degree that they themselves could be diagnosed as autistic.

Over the last 20 years, autism researchers have devised some ingenious ways of identifying some of these more subtle variants. In the early 2000s, Simon Baron-Cohen, a professor of psychology and psychiatry at the University of Cambridge, and colleagues, devised a test called Reading the Mind in the Eyes. This is intended to assess a person’s ability to detect emotions such as looking playful, comforting, irritated or bored, based on a photograph which shows only the person’s eyes.

The idea is that poorer performance on the test indicates a higher likelihood of a person being autistic. Researchers assumes that autistic individuals have a different way of looking at the face, and they seem to get more information from a person’s mouth. Neurotypical individuals seem to get more information from the eyes.

More recently, in partnership with the DNA testing site 23andMe, which agreed to host the Reading the Mind in the Eyes test on their website, Bourgeron and Baron-Cohen were able to gather data on the abilities of more than 88,000 people to read thoughts and emotions from a person’s eyes, and compare this performance with their genetic information. Through this dataset, they were able to identify large groups of gene variants associated with poorer emotion recognition, many of which are thought to be carried by autistic people. Similar to Face2Gene in recognition genetics from faces of children.

Other research studies have found that common gene variants associated with autism tend to be negatively correlated with empathy or social communication. But they are positively correlated with the ability to analyse and construct systems as well as rules and routines. Most intriguingly, they are also often linked to higher educational attainment, along with greater spatial or mathematical or artistic abilities. “This perhaps explains why these genetic variants, which come from very distant ancestors, have remained in the population throughout human history,” states Dr. Geschwind.

Extended genetic research outside of autism

In many not autism-related conditions, there exist already prenatal tests and established practice in the UK for conditions caused by having an extra copy of a chromosome in some or all of the body’s cells. These include Down’s syndrome (where there’s an extra copy of chromosome 21), Edward syndrome (where there’s an extra copy of chromosome 18), and Patau syndrome (where there’s an extra copy of chromosome 13), and in some countries like Iceland, termination rates following a positive screen are close to 100%.

A broad spectrum

Similarly, researchers, clinicians, and afflicted individuals and families in the first place aim at genetically understand autism, in order to make it prenatal recognisable and prospectively treatable. These ambitions call for a broad spectrum of efforts. The majority of the spectrum is a condition that has to be accommodated like in any other disability.

To try and better stratify the broad spectrum of autistic traits, the Lancet Commission formally recognised the term “profound autism” in 2021, as a way of describing autistic people who are unable to advocate for themselves and are likely to require 24-hour support throughout their lives. Since then, a variety of clinical trials have begun, all using various therapeutic strategies to try and target the single genes underpinning physical and intellectual disability in different individuals with profound autism.

The main idea for these treatments surrounds the fact that all of us have two copies or alleles, or variants, of every single gene, one from each parent. A recent study  leveraged the understanding that most of the de novo gene mutations linked with profound autism only knock out one of these copies, suggesting it might be possible to reduce the degree of disability by boosting the unaffected copy. That means you have one unaffected copy, the activity of sought for could be turned up to compensate,.

A clinical trial using the metal lithium was recently run to boost a version of the Shank3 gene in autistic children who are known to have Shank3 mutations. In the future technologies such as CRISPR, which allows scientists to edit a person’s DNA, could be used to intervene at an even early stage of life. For example, gene therapy could be delivered to unborn babies found to have various mutations, while they are still in the womb. Clinical researchers recently figured out a way of doing this,

The FDA has recently granted approval for the US-based biotechnology company Jaguar Gene Therapy to run a clinical trial where a gene therapy is administered to autistic children with a Shank3 gene mutation along with a co-occurring genetic condition called Phelan-McDermid syndrome which affects development, speech and behaviour. This trial is only possible because all the children participating have genetic diagnoses; researchers have spent the past 15 years studying how these children develop when they have these mutations and serve with their natural history data as a control in upcoming new studies.

But while such trials could undoubtedly result in enormous benefits for the children involved and their families, Fletcher-Watson is still sceptical about their depiction as therapies for autism, profound or otherwise. She would prefer to see them characterised as treatments for intellectual disability.

 A European project now coordinates on risk, resilience and developmental diversity in mental health, collaborating with autistic people and their families to better understand why autism rarely comes in isolation, and what makes different individuals prone to these conditions. With all the individuals ready to contribute to research there should huge amounts on genetic data be available suitable for GWAS analyses combined with AI processing in order to truly understand and care for people affected with “autism” and to truly resolve the genetic mystery behind it.

Thassohad in the past already posts on the subject of where and how portrait photos could meet genetics and AI  here, here, and here .

See here a sequence on Autism Spectrum Disorder (ASD):

Disclaimer: Images and/or videos (if any) and some text passages in this blog may be copyrighted. All rights remain with the owner of such rights.