FHU-TRANSLAD

The evaluation and the identification of a genetic cause of a developmental disease enables the optimisation of treatment and follow-up of the patient and their family due to improved understanding of the natural history of the disease and its prognosis:

• The diagnosis and identification of a genetic cause of developmental diseases
• To coordinate patient follow-up
• To propose consultations with specialist multidisciplinary teams trained in the specificity of these rare diseases
• To develop therapeutic education
• To accompany the families
• To set up genetic counselling for patients and their family

These centres propose assessment and multidisciplinary management of patients from childhood to adulthood.

Since 2013, FHU-TRANSLAD is one of the leading European centres to establish the use of genomic medicine (ES and GS in particular) in both research and diagnosis for patients with rare developmental diseases in Burgundy Franche-Comté and throughout France. FHU-TRANSLAD is also currently positioned as one of the French leaders in multiomique transfer, such as long read genome (lrGS) and RNA (RNAseq) sequencing, optical mapping and the study of episignatures.

FHU-TRANSLAD deploys these technologies in several high-expertise facilities:

From the beginning FHU TRANSLAD has positioned itself as a reference in the implantation of genomic medicine in diagnosis, using a strategy integrating clinical/laboratory and translational medicine. Its aim is to provide access to genomic medicine to all patients with rare diseases in the Burgundy Franche-Comté region who are candidates for the use of these new technologies, with emergency access if necessary. 

Over the years the activity has grown considerably, now having a staff of over 20 persons. It was in this highly dynamic context that in May 2024 the Dijon Burgundy CHU set up a new department of genomic medicine equipped as necessary for genomic activity, in the medical biology laboratory of the CHU.

This new department of state-of-the-art genomic innovation, required appropriate facilities with close ties to a research establishment. The Dijon Burgundy CHU and Burgundy University therefore jointly implanted this new site of the CHU medical biology laboratory in the UFR Health Sciences building. This laboratory dedicated to genomic medicine consists of:

•  functional unit (UF) diagnosis of rare diseases of Dijon Burgundy CHU 
•  functional unit (UF) technological innovation - NEOMICS

Head of department of medical genomics: Professor Christel Thauvin

Why set up a Functional Unit (UF) dedicated to Diagnostic innovation in rare diseases?

FHU TRANSLAD was one of the first to deploy ES in France, initially for research into the identification of new genes responsible for rare diseases, then rapidly moving to the diagnosis of rare diseases with developmental anomalies and intellectual disability for all patients with rare diseases in the Burgundy Franche-Comté region. This objective, strongly supported by the Dijon Burgundy CHU executive lead to the creation in 2016 of a "functional unit" (French hospital sub-unit, UF) dedicated to Innovation in genomic diagnosis of rare diseases (UF6254) within the laboratory hub. Subsequently, in 2015 a business unit OrphanOmiX was set up which extended access to this activity to all of France.

UF6254 activity

Over a period of several years the expertise and experience of the team became well-known nationally and internationally, and this was recognised by the inclusion of ES or GS in the care pathway of treatment for patients with rare diseases. 

The diagnostic activity consists of: 

• pangenomic analyses such as ES, RNAseq and GS. Each year, the medical genomics team analyses the ES and GS data of about 100 patients of the Dijon Burgundy CHU in the diagnosis of their rare disease. The medical genomics department has thus become a significant partner of AURAGEN laboratory (https://www.auragen.fr/) for the interpretation of GS data collected in the France Medicine Genomic Plan 2025.
• targeted genetic analyses to confirm diagnosis and the related genetic counselling for rare or ultra-rare diseases.

Following the call for projects of the DGOS (French General Directorate for the Provision of Care), this activity was nominated as reference medical biology laboratory for molecular diagnosis of intellectual disability and developmental anomalies using high throughput sequencing.

Head of the functional unit: Dr Anne-Sophie Denomme-Pichon
 

Strongly supported by the Region Burgundy Franche-Comté (FEDER), the Dijon City and the Burgundy Franche-Comté ARS (Regional Health Agency). NEOMICS is an omic technologies centre in Burgundy Franche-Comté which will provide diagnostic laboratories and research teams with access to highly innovative technologies for genomic explorations (exome and short-read (srGS) or long-read (lrGS genome sequencing), optical mapping), transcriptomics and epigenomics. They are particularly effective for high throughput diagnosis, but also for translational research in the identification of new genetic causes and epigenetic anomalies, the cause of rare diseases and cancers.

The centre is equipped with the latest genomic technologies such as the very high throughput sequencer Illumina NovaseqX+, and the Saphyr optical mapping system (Bionano Genomics). The NovaseqX+ sequencer can perform exome, short read genome and transcriptome sequencing at a lower cost, giving rise to the possibility of affordable ultra-rapid genome sequencing for any academic and/or university hospital institution. In the future the centre intends to acquire the technologies for long read genome sequencing and DNA methylation analysis for the study of episignatures.

Moreover the centre is highly robotised (2 Tecan Fluent Dream Prep automats) enable the successful performance of large high throughput projects.

Strongly supported by the Region Burgundy Franche-Comté (FEDER), the Dijon City and the Burgundy Franche-Comté ARS (Regional Health Agency). NEOMICS is an omic technologies centre in Burgundy Franche-Comté which will provide diagnostic laboratories and research teams with access to highly innovative technologies for genomic explorations (exome and short-read (srGS) or long-read (lrGS genome sequencing), optical mapping), transcriptomics and epigenomics. They are particularly effective for high throughput diagnosis, but also for translational research in the identification of new genetic causes and epigenetic anomalies, the cause of rare diseases and cancers.

The centre is equipped with the latest genomic technologies such as the very high throughput sequencer Illumina NovaseqX+, and the Saphyr optical mapping system (Bionano Genomics). The NovaseqX+ sequencer can perform exome, short read genome and transcriptome sequencing at a lower cost, giving rise to the possibility of affordable ultra-rapid genome sequencing for any academic and/or university hospital institution. In the future the centre intends to acquire the technologies for long read genome sequencing and DNA methylation analysis for the study of episignatures.

Moreover the centre is highly robotised (2 Tecan Fluent Dream Prep automats) enable the successful performance of large high throughput projects.

If you wish to discuss or submit your project, you may contact us by email and/or via the project submission form and sent it us by email at: LGM-NEOMICS@chu-dijon.fr. We will contact you as soon as possible.

Biologist: Dr Frederic Tran Mau-Them

Engineer: Mr Martin Chevarin 

 

The bioinformatics platform for the analysis of high throughput sequencing data of Dijon Burgundy CHU and Burgundy university

FHU TRANSLAD is equipped with a high-performance bioinformatics platform thanks to funding from various sources (DGOS via Rare Diseases Plan 2, Burgundy Region, CPER, FEDER). The platform is currently composed calculation servers comprising several thousand calculation cores, storage servers dedicated to calculations reaching a volume of close to 500 TB, and storage servers for the secure storage of data of a total volume of 1 PB. Installed in Burgundy University Computing Centre, they make up a standardised analysis platform accessible by several users simultaneously and the long term secure storage of sequencing data.

In view of the need for greater efficacy and rapidity, the platform was equipped with the innovative GPU-type device which reduced the calculation time by a factor ranging from 2 to 17x depending the type of analysis conducted. These processors currently analyse a complete genome in less than 10 hours, and in a few months the threshold of one hour is expected to be attained.

The development of this platform is part of a wider initiative, which aims to group together local bioinformatics and biostatistics know-how in one bioinformatics platform, BIOME, certified by the COS platform of Burgundy University and member of UMS BIOSAND certified by Inserm, in order to meet the increasing need for massive genomic and transcriptomic data analysis.

• To consolidate and develop local bioinformatics and biostatistics know-how applied to genomics and transcriptomics data.
• To aid local teams in projects requiring the massive production of data, from experimental design to analysis and interpretation of data: to develop the use of the exome for the diagnosis of patients with rare diseases with developmental anomalies
• To be used as a basis for training students/professionals and for the wider use of data analysis tools
• To develop innovative bioinformatics tools to accelerate and improve the analyses of data from high throughput sequencing/NGS.

Head of platform: Yannis Duffourd
 

Postal address

Bâtiment B3 de l’UFR des Sciences de Santé

15 boulevard Maréchal De Lattre de Tassigny 

21070 DIJON

France

The ORPHANOMIX Business Unit

Based on their experience in the use of ES for diagnosis in patients with rare diseases in Burgundy, FHU TRANSLAD next step was to propose clinical ES for the diagnosis of developmental anomalies in patients throughout France. This lead to the setup of the business unit ORPHANOMIX in 2015. Developed in collaboration with SATT Grand-Est, it is one of few structures in France to propose diagnostic exome analysis from blood sample collection to result. While positive diagnoses are sent to the reference clinicians, analysis of sequencing data for research is systematically proposed and performed by the UMR (Dual, academic-public research body) Inserm 1231 GAD (Genetics of Developmental Anomalies) research team.

Currently, OrphanOmiX remains the only French academic structure to propose the ES for diagnostic purposes to all genetic centres in France and French overseas departments and territories (DOM-TOM).

OrphanOmiX also proposes specialised bioinformatics support for establishments which wish to develop the use of high throughput sequencing/NGS for diagnosis or research on rare diseases.

Head of ORPHANOMIX: Mr Yannis Duffourd

Postal address:

Bâtiment B3 de l’UFR des Sciences de Santé

15 boulevard Maréchal De Lattre de Tassigny 

21070 DIJON

France

The ambition of the focus on "To humanise" is to mobilise stakeholders involved in the Human and Social Sciences (HSS) and Public Health (PH) in order to respond to the diverse challenges associated with the use of this technological innovation, whether these are individual or societal: challenges in terms of pertinence, feasibility, efficacy, acceptability, expectations, preferences and choice, life experience and the consequence on perceived health, efficiency, budgetary impact, accessibility and continuity of care, etc. 

These challenges are approached in this focus in the form of four distinct questions:

1. To what extent does the French population support the wider use of genetic analyses?
2. How do genetic analyses help change the real-life experience of the disease for patients and their relatives? 
3. What changes in the organisation of medical treatment and medicosocial care are needed to meet patients' needs? 
4. How to organise genetic analyses and the safeguard of their results in accordance with the choices of patients, families, and carers? 

Research projects that aim to respond to these interrogations are central to the wide and complex subject of rare diseases; a complexity exposed in the difficult and long care pathways, which concern both the health and everyday life of patients and their relatives but also in the diverse nature of the disorders encountered (developmental intellectual and communication disorders, autism spectrum disorders, learning disorders, and also motor disorders). The projects may target certain rare diseases, certain stages of the care pathway or certain points of view, or they may study a more transversal vision of the pathology or its management. 

Therefore, questions concerning this focal line are developed within the framework of several themes, including:

• prenatal use of HTS/NGS,
• neonatal screening,
• early post-natal diagnosis but also in young children and adults,
• the real-life experience of disability by patients, family-helpers and carers, 
• the question of access to additional data
• the acceptability of storage of genetic data for reuse in care and research.

The projects of this focal line depend upon having teams whose expertise in research and research support is such that they are able to conceptualise a variety of disciplines: social psychology, sociology, public health, health economics, ethics, and philosophy in addition to varied methodologies (qualitative, quantitative and both).The focus may also rely on the support and know-how of clinicians, geneticists, biologists and bioinformaticians of the sectors but also associations of relatives and patients partners in the research with whom researchers in HSS and PH interact daily in the context of their projects.

Line 5: High quality clinical, molecular, pathophysiological, ethical, organisational and societal research with a clinical and therapeutic trials centre

Therefore, FHU-TRANSLAD brings together research teams who are specialists in their fields in order to develop hubs of excellence on a nationwide and international basis, for the benefit of patients and their families. Close links have been established over the years with the UMR (Dual academic-public research body) Inserm-UB 1231, and in particular the GAD team, CIC-EC and CIC-P. 

FHU-TRANSLAD develops nationwide and international research projects around several focal lines:

Large-scale identification of new genes which cause ultra-rare diseases

The advent of genomic medicine has accelerated our understanding of the genetic causes of rare diseases, switching the identification of the causative genes responsible for disease from a strategy based firstly on the phenotype, "phenotype-first" (cohort of patients having a similar phenotype), to a strategy based firstly on the genotype, "genotype-first" (group of individuals having common genotypic data).

This "genotype first" strategy has shown its formidable efficacy in developmental diseases, in particular thanks to data sharing in a national and international scale. This strategy involves the themes of the certified reference centres on rare diseases (developmental anomalies, pathologies with intellectual disabilities, developmental maladies with psychiatric involvement, neurogenetic diseases and rare dermatological mosaic diseases devoid of obvious clinical diagnostic features), in order to better understand the genomic and pathophysiological basis of these diseases. This approach has enabled the team to identify or to help identify about 100 genes responsible for rare diseases.

Meta-analysis is a strategy which is also applied to developmental diseases, by the data sharing of thousands of patients in the European consortium Solve-RD – "Solving the Unsolved Rare Diseases", continued by the new European consortium ERDERA. Dijon Burgundy CHU is the only French centre to be a founder member of Solve-RD on the theme of developmental diseases, a 5-year research project (2018-2022) funded by the European Commission in the context of Horizon 2020. The consortium is composed of 4 European Reference Networks (ERN-ITHACA, ERN-RND, ERN-EURO NMD and ERN-GENTURIS) and 21 European academic institutions. 

In parallel with this strategy of a large-scale identification of new genes, a fine-tuned description of the phenotype of these ultra-rare developmental disorders provides us with a better definition of the clinical spectrum of the developmental anomalies. 

Development of new multiomic approaches for the identification of the molecular basis of syndromes with developmental anomalies

The use of srGS trio analysis identifies de novo and inherited events not covered by ES (intronic regions, UTRs, promotors, enhancers and other regulatory sequences) and to better identify variations in chromosomal structure having an impact on the regulation of gene expression or on the splicing of their transcripts. 

This leads to the need for additional approaches for their molecular and functional characterisation. FHU TRANSLAD, in close collaboration with the OMICS group of the UMR Inserm-UB 1231 GAD team, develops progressive and personalised integrative and multiomic studies, including srGS and long-read GS (lrGS), optical mapping of the genome, transcriptome (RNAseq) and epigenome analyses in patients with rare neurodevelopmental syndromes, for whom the srGS trio analysis has remained negative (PPR MultiOmixCare). 

Moreover, for some events undetectable by standard srGS, high throughput long read sequencing technologies (Oxford Nanopore, PacBio, 10X Genomics) or long-reads, may be performed. An approach combining these new technologies and the use of neurons derived from induced pluripotent stem cells (iPSCs) obtained from patients may enable the identification and understanding of the clinical relevance of the new variations. The deployment of these technologies at the forefront of genetic innovation is conducted in close collaboration with the French National Centre for Research in Human Genomics (CNRGH).

Development of bioinformatics applied to high throughput sequencing and to multiomics

This development is performed by the deployment of graphics processing units (GPU) which are a currently underused technology for accelerating calculation times of bioinformatics analyses. Some studies have demonstrated that for some bioinformatics applications, the run times could be divided by 10 when calculations are performed with GPUs. The very rare tools in existence do not meet requirements nor the current evolution of HTS/NGS. The development of new bioinformatics tools using this type of architecture will therefore be a major step forward in modern bioinformatics applied to human genomics, thus greatly decreasing the response time for diagnosis using these analyses. 

Pipelines dedicated to the analysis of data using short read GS (srGS) and RNAseq have also been developed, with several data integration programmes (OMIXCARE, INTEGRA and MultiOmixCare). 

Moreover, the evaluation of 3rd generation high throughput sequencing technologies (Chromium, 10X, Oxford Nanopore, PacBio) for the identification of structure variations is also a major development focus.

Acceleration of the implementation of GS in neonatal diagnosis and screening for rare diseases

For several years FHU TRANSLAD has invested massively in this direction in close collaboration with PFMG2025, both in pilot feasibility projects to identify and remove obstacles, but also by evaluating the value of GS in certain indications or specific clinical situations, in particular by the coordination of the first pilot project using rapid GS for diagnosis in new born infants hospitalised in neonatal ICU.

It is currently implementing 3 major projects on genome sequencing:

• the first pilot project of genome sequencing by ultra-rapid (<7 days) trio analysis compared with the combination DNA-chip based chromosomal analysis (CMA) and rapid exome trio (<28 days) in the context of prenatal diagnosis of malformation syndromes (PRENATOME-ULTRA).
• the evaluation of the value of high throughput long read genomic sequencing for the causal diagnosis of cerebellar ataxia (ALICA).
• the pilot project to evaluate the feasibility and social acceptability of extending neonatal screening in France to several hundred rare diseases via the targeted analysis of a list of genes from genome sequencing (PERIGENOMED).

This major investment in transfer of GS to neonatal diagnosis and screening is conducted in close collaboration with PFMG2025 and PNMR4 to accompany the implantation of very high throughput laboratories and the deployment of genomic medicine in France. 

Development of a clinical and therapeutic trials centre

TRANSLAD-Treat is a therapeutic trials centre designed for patients with developmental and neurodevelopmental diseases.

The centre is specialised in the implementation of therapeutic trials in developmental diseases with segmental mosaic hypertrophy and neurodevelopmental diseases.

In the field of rare diseases, the identification of a cause of the pathology of an individual patient is a crucial step, which has been greatly improved with the arrival of high throughput sequencing technologies. To reach a diagnosis will sometimes require a series of research steps of varying difficulty. The identification of a genetic defect may lead to a therapeutic option. Progress in preclinical research in private or public laboratories contribute to the selection of potential new or existing molecules. This leads to clinical trials allowing patients to benefit from scientific and medical progress. 

TRANSLAD-Treat has coordinated or is currently coordinating 4 international therapeutic trials in developmental anomalies with segmental hypertrophy or neurodevelopmental diseases:

• Sirolimus and PIK3CA-associated segmental hypertrophy (PROMISE, Sponsor Dijon Burgundy CHU).
This phase II open-label proof of concept study aiming to study the efficacy of sirolimus in PIK3CA-associated segmental overgrowth was conducted using the same protocol in 3 centres (Dijon, Cambridge, Bethesda). Published study: PMID: 30270358

• Taselisib and PIK3CA-associated segmental overgrowth (TOTEM, Sponsor Dijon Burgundy CHU). This phase Ib/IIa study consists of the assessment of the safety and efficacy of taselisib, a direct inhibitor of PIK3CA, in 30 patients with segmental mosaic hypertrophy, in France and the UK. Published study: PMID: 34385668

• Alpelisib and PIK3CA-associated segmental hypertrophy PIK3CA with cerebral involvement (SESAM, Sponsor CHU Dijon Burgundy): Double-blind phase II, multicentre, placebo-controlled trial, to assess the efficacy and safety of alpelisib (BYL719) in paediatric and adult patients with megalencephaly-capillary malformation syndrome (MCAP). Financing, Novartis 2022. NCT05577754

• Lithium and TBR1-related neurodevelopment syndrome (ESALIT: Sponsor Dijon Burgundy CHU): A pilot, multicentre, controlled, open-label study evaluating 24 months of lithium carbonate treatment in patients with TBR1-related neurocognitive disorder. Financing, PHRC national 2022. Start of inclusions scheduled for 2025.

TRANSLAD-Treat has also participated in or is currently participating in various therapeutic trials in France in developmental diseases, sponsored by academic or industrial bodies: FRAGXIS (Sponsor ROCHE), EPIK-P1, EPIK-P2, EPIK-P3 (Sponsor NOVARTIS).

The team is currently studying databases which reveal the natural history of some developmental anomalies for which treatment may be available via compassionate access or early access:

• Improving the understanding of the natural history of patients with Kosaki/Penttinen syndrome and the impact of treatments with tyrosine kinase inhibitors. Funding AnDDI-Rares 2023 and OSCAR 2024. NCT05953857.

• Epidemiology and natural history of a French cohort of patients with Allan-Herndon-Dudley syndrome having a pathogenic variant of the SLC16A2 gene, treated or not. Financing, Egetis 2024.