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Call for research projects: “Human and social sciences & rare diseases”

The Foundation for Rare Diseases is launching its 9th call for research projects: “Human and social sciences & rare diseases”.

As part of the Foundation’s participation in the RHU project ‘COSY’, 4 projects addressing the challenges of patients affected by Overgrowth Syndromes (OS) will be supported for up to 12 months and with a maximum budget of €20,000.

All projects should formulate a research question, the benefits of which being transposable to other pathologies, involving at least a research team in Humanities and Social Sciences (HSS), a medical team specialized in rare diseases and a patient advocacy group. Finally, the bearer must be an expert in the HSS field. All rare diseases of children and adults are concerned.

Click here to find more about this projects call: https://fondation-maladiesrares.org/wp-content/uploads/2021/05/SHS9-Call.pdf

Interview of Dr. Stéphanie Baulac

Inserm research directoris and head of the research team at the ICM (Paris Brain Institute in French Institut du cerveau – ICM)

→ Who are you?

I am a geneticist intrigued by mosaic mutations in epilepsies with cortical malformation.

→ What is your role in the project?

I am the leader of WP2, which aims to tackle the genetic etiology of these syndromes and to contribute to the genetic diagnosis. Using the latest generation sequencing tools, we are looking for mosaic mutations that are only present in a small number of cells.

I am also involved in WP3 which aims to understand the physiopathological mechanisms of these syndromes. The goal is to develop preclinical mouse models, modelling somatic mutations in vivo in order to test new pharmacological targets.

→ Currently, what are you working on?

We are now working on a cohort of young patients with a cortical malformation (particularly focal cortical dysplasia), who have undergone resection of the epileptogenic focus to control their epileptic crises. 
Using a targeted sequencing panel, we have identified numerous somatic mutations in various genes (MTOR, RHEB, PIK3CA, AKT3, TSC1 / 2) of the mTOR signalling pathway, which controls cell growth and proliferation. These mutations are “brain-specific”, they appear during brain development. Thus, somatic mosaicism is gaining more importance in several diseases besides cancer.

→ What are your first discoveries?

Our recent work has shown that there is a gradient of mosaicism correlated with the size of the dysplastic lesion in the brain. The earlier a mutation occurs in brain development, the larger the fraction of cells and the lesion will be extensive (Lee * Baldassari * et al. 2021). By laser microdissection of cells, we have demonstrated that only abnormally large cells carry the mutation. 
We were also interested in a subgroup of cortical malformations, “mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)” and showed that somatic mutations in the SCL35A2 gene, which codes for a galactose transporter are responsible (Bonduelle et al. 2021).

→ What is the impact of your work on the project?

This work makes it possible to offer a genetic diagnosis to families, a reclassification of these cortical malformations based on genetic etiology, but also to evolve towards precision and personalized medicine, which is based on the understanding of deregulated signalling pathways.

What is next?

The remainder of the work consists of looking for new genes by a so-called “whole exome sequencing” approach in patients who are panel-negative, in order words who do not carry mutations in genes known to date



〉 Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) – Bonduelle et al. acta neuropathol commun
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〉  Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia – Annals Clinical and Translational Neurology
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The detection of the mutation PIK3CA

Interview of the Pr Guillaume Canaud

→ What is a gene panel? 

A gene panel is a test that analyzes multiple of genes at once. The goal is to identify a mutation that explains the disease. In such analyze we are focusing on a subset of genes known to be associated with overgrowth syndromes. Having a negative test does not exclude a mutation. This can be due to the sensitivity of the test that is not sufficient or the biopsy ran could have be performed in an area that is less/not affected by the disease or the disease can be related to a new gene that is not know yet.

In case of a negative test, we perform a second or a third biopsy. If on these subsequent tests we don’t find any genetic explanation we perform a whole exome sequencing (i.e. we explore all the genes and not only the ones from the panel). 

→ Which medical centers can run this test?

Each medical center has his own panel. Most of them are dedicated to oncology since the genes involved in overgrowth syndromes are similar (PIK3CA, AKT, mTOR, RAS….). However, usually that kind of panels do not allow to explore very low frequency variant. Dedicated panel to overgrowth syndromes are indeed mandatory.

→ Is there a universal gene panel for all overgrowth patients?

Absolutely not! This is our goal. We aim to purpose a panel to all medical centers taking care of patients with overgrowth in order to cover more than 90% of the genes involved.

→ Which type of samples is necessary to run this test?

This is mandatory otherwise you will miss the mutation. As stated above, a negative test does not exclude the presence of a mutation. Sometime, a second or a third biopsy is required. 

→ Can PIK3CA mutation always be detected by using a gene panel?

It depends on the design of the panel. Most of the time yes.

→ What other mutations can it detect? 

We have two different panels that we are using now. The first one is used daily to detect mutations in patients with overgrowth and/or vascular anomalies. In this panel we test the following genes:AKT1 AKT2 AKT3 BRAF GNAQ KRAS MAP2K1 MTOR NRAS PIK3CA PIK3R1 PIK3R2 RASA1 TEK TSC1 TSC2 GNA11, GNA14, HRAS, MAP3K3, KRIT1, EPHB4, PTEN. The second panel is a research panel exploring more than 50 genes involved in the PIK3/AKT/mTOR pathway.

At the end of the project by merging the data obtained from these 2 panels we will be able to provide an optimized test for patients with overgrowth.

→ What have you already discovered?

We found new mutations but they are currently under investigation to validate their pathogenic potential. We also found that few patients are carrying additional mutations.

Interview of Prof. Guillaume Canaud

What is your role in this project?

I am the scientific coordinator of this consortium which brings together over a dozen of academic partners, hospitals, private companies, and a Foundation. This sort of research consortium is unique and a specific French feature.

→  What are your motivations?

It’s a taxing question! I’ve always been drawn to science, understanding how a disease works, but also very excited by novelties. Moreover, I am very sympathetic to the issue of disability in this type of pathology, the consequences are very significant. In addition to the symptoms of the disease such as pain or bleeding, repeated hospitalizations and surgeries, the social repercussion is major with far too often children and adults discriminated because of physical disabilities and are thus on the margins of society. Lastly, when you see the enthusiasm of the different teams involved (research laboratory, paramedical and medical staff…) your motivation is increased tenfold!

Which disease are your work focus on?

We are currently working on a group of pathologies responsible for overgrowth syndromes. Of course, we have a particular interest in mutations of the PIK3CA gene involved among other things in CLOVES syndrome or venous and lymphatic vascular abnormalities, but also in genes called AKT1 (responsible for Protea syndrome) and his cousins AKT2, AKT3 and mTOR. This project is also expected to identify new genes and possibly new therapeutic avenues. Indeed, this is one of the major challenges of the project, which involves repositioning treatments developed for other pathologies that could be beneficial in these syndromes, as we have already demonstrated.

How do you intend to study it?

Thanks to this funding, we have a unique opportunity to bring altogether different categories of research (clinical, fundamental, genetic, radiological, computer…) around the same type of pathology. In my opinion, the key element in this kind of project is to have patients and basic research on the same place (new mouse models, new genes identified…). That’s what we came to create on the Necker campus.

What are your hopes and goals for the future?

This is a very promising project since it will provide a better understanding of these diseases and help to identify new markers of the activity of these diseases, to identify new therapeutic targets, to find new genes involved in these syndromes, to improve the integration of patients into society and finally to make these pathologies known to the medical community in order to improve their cares.

Kick-off meeting of RHU-COSY Project

We were pleased to gather all team members at the Institut Necker – Enfants Malades (INEM) on Mach 2nd 2020 to launch out the RHU COSY project.

It was a very enthusiastic and productive meeting where we had the opportunity to make introductions, present the work packages, and get to know each other’s roles on the project. Other practical aspects such as context, overall goals, and timelines were discussed.

We all have started working towards a common goal of transforming the outcome and the medical care of patients with overgrowth syndromes and we will keep you updated on the progress and the upcoming events of the project.

First meeting of the partners

The first meeting of the RHU COSY project was held at Institut Necker – Enfants Malades (INEM) on December 10th 2019 and brought together member of the consortium for a first presentation of the project. 

RHU COSY gathers together 11 partners and 1 patient association, combining all the necessary skills to propose innovative tools in physiopathology, genetics, imaging, and care reorganization. Our goal is to re-define medical care and offer a unique multidisciplinary service dedicated to patients with Overgrowth Syndromes (OS).