Genetics shed light that there is not just one type of autism

Lee Daily: How did you come to explore the genetic pathway in autism when France was so cautious about these approaches?

Thomas Bourgeron: As early as 1977, studies of twins argued in favor of genetic components in autism. But until the early 2000s, we didn’t know which genes might be involved.

I was not originally an autism researcher. I started with plant biology and then joined groups at Necker Hospital (AP-HP) and at the Pasteur Institute. At the Pasteur Institute, I identified a new gene in an important area for schizophrenia: even if this research was unsuccessful, it was my first contact with psychiatrists and autism, an area of ​​research I would turn to next.

Looking into a Swedish family with two siblings with autism (one with Asperger’s Syndrome), I discovered a mutation in the neuroligin 4 (NLGN4X) gene located on the X chromosome; This is a “stop mutation” that prevents the synthesis of the protein encoded by this gene and leads to its loss of function. It was the first time this mutation had appeared! Then we found another, in another gene, neuroligin 3 (NLGN3X), also on the X chromosome, in another Swedish family with two children with autism. But our article published in 2003 doesn’t make much noise…

A few years later, with student Christelle Durand, we identified the Shank3 gene, which also codes for a synaptic protein and is switched on in autistic people with severe cognitive disorders. This publication in 2006 is a landmark. We then highlight the involvement of neurexins (NRXN), neuroligins’ partners. In 2007, we have a few pieces of the puzzle in which the synapse—the connection point between neurons—plays a key role. Since then, technologies have improved. More than 200 genes implicated in autism have been identified.

The work on autism in France is complex, and even more so in genetics. The Pasteur Institute trusted me with accepting, in 2003, the creation of a “five-year cohort” that became a laboratory for about fifteen researchers, psychiatrists, neuroscientists and geneticists. Genetics makes it possible to understand that there is no single type of autism, and therefore no single type of comorbidity.

All of these genetic differences do not have the same significance on autism risk. What do we know today?

Our findings consist of showing that a single gene mutation can lead to a severe form of autism and that it modulates the number and function of synapses. We find mutations again In 20 to 25% of children with autism and severely affected intellectual disability. Evidence suggests that genes that are expressed early, before birth, lead to more severe cognitive impairment.

The more patients we analyzed, the more autism-related genes we found, but more research is needed in this area because some mutations are variations of unknown significance.

As for the polygenic forms resulting from the addition of many genetic variations in a person’s genome, we find people with autism without an identity like Asperger’s syndrome, but we are only at the beginning of understanding them.

With Professor of Psychology Simon Baron Cohen (Cambridge), we tested 700 twins for empathy. They had to decipher feelings through people’s eyes. We found 30% of heritability indicates that genetic differences explain part of our ability to read minds in the eye!

We put this test (reading the mind in the eyes) as well as questionnaires to assess the level of empathy on the genetic platform 23andMe and received a total of more than 80 thousand responses. On average, the autism genome is depleted in genetic variations that give high scores for empathy. But there are many differences that come into play…not everything is hereditary. These genetic differences, which are not directly related to autism or empathy, will more or less increase the likelihood of developing autism or having difficulties in acquiring language and understanding the feelings of “the other…

Why are you looking for genes?

Finding genes helps identify biological pathways that function unusually in people with autism. The first genes we found (NLGN, Shank, NRXN) form a synaptic pathway; The other pathway is the one that allows for gene regulation via Chromatin remodeling. Each time, the result of these genetic differences appears to be a modulation of neuronal and synaptic plasticity. The property of synapses to strengthen or weaken the ability to pass from one nerve cell to another.

From there, we were able to make cellular models (for observing synapses) and animal models. We have worked on mice transgenic in these genes, in particular Shank3; My group with Élodie Ey and Fabrice de Chaumont was the first to show that they speak differently and less, which is also accompanied by problems in social interactions.

And the discovery of genes and biological pathways makes fathers (especially mothers!) feel guilty. Families affected by the same genes were able to meet in institutions and share their experiences. This knowledge also helps researchers move forward … I have nothing against psychoanalysis – my father was a psychoanalyst – but in autism it has the opposite role. Implementation of the behavioral techniques was slow, and parents withdrew their children on suspicion of abuse. Europe has repeatedly condemned France for its delay.

What role can genetics play in treatment?

We are working on animal models in hopes of understanding how atypical brains communicate or why they experience epileptic seizures, and thus improve some cognitive abilities or reduce comorbidities.

We can look for molecules that can modify the manifestations of autistic disorders. For example, in collaboration with Alexandra Benchoua of the Institute for Stem Cells for the Treatment and Study of Monogenic Diseases (I-Stem), we have successfully reconstructed neurons from patients carrying a mutation in Shank3 (from stem cell-derived skin pieces), which were found to contain On fewer synapses (as expected). Alexandra tested 205 existing molecules and found that lithium enhanced the expression of Shank3 and synapses.

Lithium is probably not a miracle molecule, but several cases of positive responses to treatment have been reported in the literature. However, it is necessary to quantify these observations objectively with a robust lithium study. Opposite placebo. So in 2022, Pr Richard Delorme and the team at Robert-Debré Hospital (AP-HP) began the Lisphem Study, the first randomized, double-blind trial targeting 22 young patients, carriers of a Shank3 mutation. Results expected in 2024.

Could genetic testing have its place in the screening strategy?

They cannot alone constitute diagnoses of autism (which must be made by a multidisciplinary team), but they can provide support for a better understanding of the autism category to which an individual belongs, in particular for inclusion in clinical trials.

You are involved in many European research projects. that ?

The Aims-2-Trials project, funded by Europe and pharmaceutical companies, involves three groups to follow people (ages 0 to 30) over a long period of time, to see how autism develops and to look for biomarkers.

The second project, Candy, consists of studying comorbidities in autism by focusing on siblings.

The R2D2-Mental Health project (Risk, Resilience and Developmental Diversity in Mental Health), funded by €10 million and brings together 20 research centres, aims to understand the trajectories of people with neurodevelopmental disorders. Our goal is to change the very simple equation: risk = prognosis. In addition to risk factors (for example, being a carrier of a mutation or being born prematurely), we study factors of flexibility, neurodevelopmental diversity, quality of life, etc. to understand why some people perform better than others. Others face the same risks. This is by fully involving the people involved!

Finally, at the French level, we are pleased that the Genomic Medicine 2025 plan opens the way for the first complete genomes of people with autism. France must do more for children in difficulty. We await the results of our application for a University Hospital Institute (IHU), in collaboration with Robert Debre.

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