A new diagnostic era thanks to advances in genetics?
Rare genetic disorders affecting the development of the nervous system are extremely heterogeneous, both in terms of their mechanisms and their manifestations. More than 7,000 rare disorders are currently listed, including around 800 of neurological origin. A significant proportion of these relate to neurodevelopment, i.e., how the brain and nervous system develop and function during childhood.
In this context, diagnostic uncertainty is common. Nearly half of children with neurodevelopmental disorders do not receive a precise diagnosis. Months or even years can pass between the first symptoms and the identification of the possible genetic cause. During this period, families consult numerous specialists, undergo repeated and sometimes invasive tests, and are left without clear answers to their questions. This uncertainty fuels anxiety, guilt, and sometimes a feeling of isolation, even though parents have long sensed that “something is wrong” with their child.
The emergence of genetic sequencing has profoundly transformed this landscape. Sequencing of the exome (the coding part of genes) and the entire genome now makes it possible to analyze millions of DNA fragments in parallel. When a variant is identified, it is then interpreted, classified, and evaluated by a team of geneticists and clinicians for its pathogenic potential.
These technologies now represent a concrete tool for making diagnoses that were previously considered almost impossible. They make it possible to name a disease, identify a disrupted biological pathway, and even refer patients to clinical trials or research programs. However, they are not yet available to everyone. Their cost, the need for highly specialized expertise, and the organization of healthcare systems still limit their widespread use.
Early detection: the key role of warning signs
In practice, the starting point is almost always the parents' observation, as they are often the first to detect subtle signs. Every symptom warrants a pediatric evaluation to distinguish between normal variability and worrying signs. Certain “red flags” warrant referral to a pediatric neurologist...
However, these specialists are rare in some cantons, which lengthens delays and increases the risk of delayed diagnosis. This highlights the importance of training general pediatricians to recognize these early signs in order to speed up access to investigations. Identifying the disease does not solve everything, but it does put an end to doubt, allows the appropriate resources to be mobilized, and sometimes opens up access to specialized trials or networks.
Towards better structured care
Once the diagnosis has been made, challenges remain. The rarity of these conditions means that few protocols have been established: doctors must adapt their care to unique situations and deal with a high degree of uncertainty. Care pathways are therefore developed on a case-by-case basis, involving multiple disciplines.
Faced with these challenges, Switzerland has been gradually structuring the management of rare diseases over the past decade. The Swiss Rare Disease Registry, operational since 2020, is a key step in this process, as it identifies the people affected. One of the expected developments is the establishment of a coordination center responsible for data management. In September 2025, the Federal Council proposed a law establishing a mandatory federal registry, including the systematic reporting of new diagnoses. This enhanced registry, managed by the coordination center, will make it possible to better document the epidemiology of rare diseases in Switzerland and to support research and specialized networks.
At the same time, the federal government and the cantons have begun to recognize and support centers of expertise and multidisciplinary networks. University hospitals play an essential role in this. In French-speaking Switzerland, a prime example is the CORAIL Center at the HUG, which opened in January 2023. This innovative structure supports children with rare or complex diseases and places families at the heart of the care pathway. CORAIL coordinates the various medical, paramedical, and social stakeholders. However, the initiative remains fragile, dependent on limited human and financial resources.
Another essential pillar is access to reliable, centralized information. The international Orphanet portal plays a key role in this regard. The Swiss section is coordinated by the HUG and centralizes information on rare diseases, expert centers, available tests, and patient associations, facilitating guidance for both families and doctors.
A rapidly changing therapeutic landscape
While many of these diseases remain incurable today, medical research is progressing rapidly. Several innovative therapeutic approaches are opening up new possibilities. Three main areas are emerging today: gene therapy, antisense oligonucleotides (ASOs), and drug repurposing. Each illustrates a different way of capitalizing on advances in genetics and molecular biology.
Gene therapy
Gene therapy, first and foremost, aims to correct the defect causing the disease by introducing a functional copy of the altered or defective gene. In Switzerland, centers such as the CHUV in Lausanne are participating in international clinical trials. Although promising, this precision medicine still faces regulatory, cost, and logistical constraints and raises questions of equitable access. But it opens up a new avenue: treatments that directly target the genetic defect causing the disease, rather than merely managing the symptoms.
Antisense oligonucleotides (ASOs)
Antisense oligonucleotides represent another major advance. These are short sequences of modified DNA or RNA, designed to bind specifically to the messenger RNA produced by the gene in question. By attaching themselves to this RNA, these molecules can modify its splicing, restore correct reading, reduce the production of a toxic protein or, conversely, reactivate an underexpressed gene. This principle offers great flexibility, as it is possible to finely adapt the strategy to the specific mechanism of each mutation.
One of the most innovative aspects of this approach is the possibility of designing “N=1” treatments, i.e., treatments customized for a single patient. Researchers, particularly at the HUG, are already working on ASOs targeting genes involved in rare childhood diseases, with encouraging initial results. ASOs represent one of the most promising avenues in pediatric precision medicine.
Drug repositioning
Drug repositioning is a third, equally interesting avenue for rare diseases. It involves using existing drugs to correct the molecular consequences of a rare genetic mutation. The process begins with a cellular analysis to identify the molecular defect caused by the mutation. From there, databases of thousands of molecules already on the market are consulted and integrated into a sequence to see if they can be used in the context of the diseased gene.
This process, developed by a team at UNIGE, has identified several promising molecules in certain genetic encephalopathies. A particularly significant example is the GNAO1 gene, mutations of which can cause severe motor disorders and early-onset epilepsy. The molecule identified to stabilize the deficient protein is zinc. This offers a concrete avenue for treatment based on targeted drug repositioning that is easily administered. This type of result shows how it is possible, by relying on already known molecules, to make faster progress towards therapeutic avenues for diseases that previously had no options. This strategy has the advantage of accelerating development stages and reducing costs, while opening up prospects for a significant number of rare diseases.
Conclusion
Rare genetic neurodevelopmental disorders are currently at the crossroads of several dynamics. On the one hand, they highlight the current limitations of healthcare systems: scarcity of expertise, delays in accessing diagnosis, costs, etc. On the other hand, they are benefiting from scientific advances, with the rise of genetic sequencing, the development of coordination structures such as the CORAIL Center, and finally the arrival of new targeted therapies that show promising momentum.
The Hôpital de La Tour Foundation committed to research
The Hôpital de La Tour Foundation is actively committed to medical research, notably by supporting innovative projects led by researchers at the University of Geneva. It is in this context that it supports ongoing work on drug repositioning. You too can contribute to advancing research. Every donation counts.