Genetic Psychiatry in Action

Complex and heterogeneous syndromes par excellence, pervasive developmental disorders (PDDs) pose a significant challenge for researchers, particularly in the field of genetics. Autism, however, is a highly heritable disorder: the recurrence risk in families of individuals with autism is 45 times higher than in the general population, and when one monozygotic twin is affected, their sibling has a 60% risk of also being autistic. Despite this strong genetic influence, research has long hit a wall, failing to identify any gene involved.

How can we explain this lengthy period of trial and error? "Environmental and epigenetic factors, meaning changes in cellular access to a gene sequence without modifying that sequence, likely interact with a genetic predisposition involving several risk genes," explains Nicolas Ramoz from U675 "Phenotypic, Developmental, and Genetic Analysis of Addictive Behaviors" (Bichat, Paris). But how many genes are involved? We’re not sure, though, as Eric Fombonne, former Inserm researcher and now at McGill University in Montreal, points out, “some predictive models estimate 3 to 20 major genes.”

Another difficulty arises from the fact that studies have long been conducted on samples that were too small, too heterogeneous, and often clinically poorly characterized. Marion Leboyer, head of the Genetic Psychiatry team of U513 "Neurobiology and Psychiatry" in Créteil, confirms that she had to develop new methodological approaches: “In 1992, we established a European collaboration bringing together teams specializing in childhood autism, including Professor Christopher Gillberg’s team in Gothenburg, Sweden. This study, which I coordinate and is named the Paris Autism Research International Sib-Pair Study (PARIS), has enabled us to gather a large sample of families and patients—currently exceeding 500 families with one or two affected children. In 1999, we conducted one of the first genome screenings on a sample of 50 families with two affected children, identified candidate regions, and searched within these regions for candidate genes.”

A Breakthrough

The year 2003 marked a breakthrough with the discovery, published in Nature Genetics, of two genetic mutations in two families where two boys were affected, one with autism and the other with Asperger syndrome: mutations in NLGN3 and NLGN4, which prevent the formation of neuroligins, cell adhesion proteins located at synapses. This suggests that a defect in synapse formation could predispose individuals to autism. “These genes were indeed found on the short arm of the X chromosome, one of the candidate regions identified during genome screening in the PARIS study. This success was made possible through collaboration with Thomas Bourgeron from the Institut Pasteur in Paris.”

"Since this mutation has been found in both autism and Asperger syndrome patients, we are extending our work to this syndrome," adds Marion Leboyer. “This pathology is still poorly understood and rarely diagnosed in France. Therefore, we will open a specialized consultation for these patients to offer them clinical, cognitive, and somatic evaluation, as well as specialized care. Once again, we hope for results from this approach that moves from phenotype to genotype. And concerning neuroligins, their discovery now encourages us to take the ‘reverse journey,’ from the NLGN genotype back to the phenotype…”

More and More Candidates

As always, the most crucial part is that these findings have been replicated by other teams. This includes Christian Andres's team from U619 "Dynamics and Pathology of Brain Development" in Tours, which showed that the NLGN4 gene is implicated not only in autism but also in certain forms of intellectual disability. This suggests that in some cases, the two conditions may have common genetic origins. The researcher from Tours explains the approach for testing specific candidates: “There have been genome-wide screenings, but these are expensive and often not very conclusive. However, cross-referencing five such screenings has identified regions of interest on chromosome 7, where we are currently focusing our research. On the other chromosome of interest, chromosome 17, candidate genes were selected based on other criteria. For instance, 5 to 10% of children with autistic disorders show chromosomal abnormalities, such as breaks, duplications, and translocations. Three genes already appear to be involved in intellectual disabilities associated with autism. We can also base our research on biochemical anomalies found in autistic individuals, often affecting receptors or transporters, particularly for neurotransmitters like serotonin and glutamate. This led us to identify a locus of interest on chromosome 17. Currently, we are evaluating a total of about fifty candidate genes.”

Gender differences in autism prevalence—boys are four times more affected than girls—also lead to a focus on the X chromosome. Another approach involves examining related syndromes, such as neurofibromatosis, tuberous sclerosis, and fragile X syndrome, which are associated with autism in 10 to 50% of cases. Fragile X syndrome, the most common hereditary cause of intellectual disability and autism, is the primary focus of Barbara Bardoni, CR1 Inserm at UMR 6543 at the University of Nice-Sophia Antipolis. With her team, she has focused on the FMRP protein (Fragile X Mental Retardation Protein), absent in patients with fragile X syndrome. She has shown that its cytoplasmic partner, CYFIP1, interacts with the RAC pathway, known to be involved in intellectual disability. Interestingly, knocking out CYFIP in fruit flies causes issues with axon and synapse organization. In humans, CYFIP1 is located on chromosome 15q11-13, a region associated with syndromes characterized by intellectual disability and/or autism.

"Since CYFIP1 appears to be a potential candidate gene for autism, our team is working to understand the molecular mechanism underlying the regulatory pathways: Rac-CYFIP1-FMRP and mGluR5-FMRP-CYFIP1. We are also investigating any variation in CYFIP1 expression in autistic patients selected in collaboration with the CRA in Nice, the Genetics Department at Archet 2 Hospital (with Dr. Houda Karmous-Benailly) in Nice, as well as the Consortium being established by Nicolas Ramoz and Michel Simonneau (U675).”

More Efforts Ahead

The goal is not simply to identify genes. Ultimately, it involves combining genetic and imaging observations to refine diagnoses, better characterize patients, and guide them towards more effective care and therapeutic strategies. These examples highlight the essential cohesion that must exist among researchers in fundamental disciplines, clinicians, and families. Marion Leboyer says, “It has always been a priority for me to maintain this integration between clinical practice, clinical research, and fundamental research. But setting up cohorts, networks, or specialized consultations requires substantial resources and time. Without additional funding and the support of patients and their families, we won’t succeed.”

"Parents are very eager but also very motivating and active in supporting and directing research," adds Catherine Barthélémy (U619, Tours). Without the various family associations and foundations like the Fondation France Télécom and Fondation de France, genetic psychiatry research in France would not be where it is today. "We rank third internationally in terms of publications, behind the United States and the United Kingdom," says Christian Andres. "We’re doing relatively well with limited resources. But looking at the tremendous momentum in the U.S., it’s clear that significant efforts in funding and recruitment are essential if we don't want to fall behind."