The ROHHAD EPIGENETIC Project

This project is dedicated to the epigenetic study of patients with ROHHAD Syndrome, in addition to their genomic analysis. The aim is to highlight regions of the genome that would show epigenetic alteration in ROHHAD patients.

The central dysregulations observed in the Syndrome are indicative of hypothalamic dysfunction. Understanding the underlying disturbances, such as the identification of an epigenetic mechanism, will allow progress in the understanding of physio-pathological mechanisms and biological pathways that could be targeted by a possible therapy.

Our project is dedicated to study the epigenetics of patients with ROHHAD Syndrome, in addition to their genomic analysis. The aim is to highlight regions of the genome that would show epigenetic alteration in ROHHAD patients.

This project follows a preliminary study which encouraged us to increase the number of patients in the cohort. The first goal is to include 10 ROHHAD patients. From these data, we will search for common pathways that are affected by epigenetic modifications in ROHHAD patients. Additional genetic and epigenetic analysis of the tumour biopsies in the case of ROHHAD patients who have undergone an earlier surgery for ganglioneuroma could be considered and performed in our study to enhance our data with somatic results..

How can you participate?

For this study, we need a blood sample from ROHHAD patients, with an established ROHHAD diagnosis. We would like to analyze in first intention ROHHAD patients at the time of the diagnosis, but all ROHHAD patients could be included. We need a blood sample from the patient but also from both parents and if possible from sibling. The blood sample is taken at the usual health center, and a shipment is organized to collect the samples at the University of Liège, Belgium.

If you are interested or would like to have more information’s; please write to Julie.Harvengt@chuliege.be

As an added value, the technical protocol used to perform the genomic analysis (rWGS) allows us to obtain rapid results (7 to 14 days, depending on the shipping time). It is especially dedicated for ROHHAD patients who would be hospitalized in pediatric intensive care unit at the time of diagnosis. This analysis is also highly useful for intensivist to rule out other differential diagnosis.

Meet the Team

This project includes an interdisciplinary approach with connections between the following participating teams from the University of Liege, Belgium and from Diagenode.

This project is funded by a grant of the FNRS Belgium, a grant from the “Léon Frédéricq Fundation” (University Hospital Foundation in Liege) and the financial support of the Belgian Rohhad Association.

Medical Team

Research Team, Human Genetics:

Etiopathogenic hypotheses - Brief description of the current knowledge.

The aetiology of ROHHAD Syndrome is currently not determined. Hypotheses have been put forward with the possibility of genetic mechanisms, paraneoplastic or autoimmune processes or epigenetic alterations.

The genetic hypothesis has been investigated without any evidence of a specific candidate gene. Research is currently being pursued on genomic studies by some international teams. They may provide details on non-coding regions or detect CNVs (copy number variations).

The hypothesis of a paraneoplastic process is put forward in view of the presence of neuroendocrine tumours in 56% of patients. This hypothesis is discussed since not all ROHHAD patients systematically present an evolution towards tumour involvement.

The hypothesis of an autoimmune process is retained on the basis of observations, in particular the detection of oligoclonal bands in the cerebrospinal fluid of certain patients and a case described with lymphocyte infiltration in the hypothalamus. Some patients are also described with a favourable initial response to immunosuppressive treatment such as cyclophosphamide or Rituximab°. The difficulty lies in establishing reliable measurements that can identify inflammatory and autoimmune processes. The measurement of hypothalamic or pituitary specific autoantibodies is until now difficult to interpret.

The hypothesis of an epigenetic mechanism was essentially suggested by the observation of a patient with an unaffected monozygotic twin. For monozygotic twins, the accumulation of variation in their epigenome throughout their lives is the factor which mainly influences their phenotype difference. Moreover, epigenetic mechanisms have a well-established role in the genesis of cancers. On the other hand, they are also increasingly studied for paediatric pathologies and epigenetic mechanisms. For example, the Prader Willi Syndrome (PWS), in which genes are subject to parental imprinting. A study has carried out the sequencing of the genes included in the PWS region, without identifying any mutations in patients with ROHHAD syndrome. However, this study did not analyse the expression of these genes, which can be altered by epigenetic mechanisms. A particular attention should be paid to this genomic region when studying the methylation profile (epigenetics). Finally, the appearance of the pathology a few years after birth may indicate a potential environmental role that would influence gene expression via epigenetic regulations

The ROHHAD EPIGENETIC Project is dedicated on this epigenetic hypothesis in the hope to better understand physio-pathological mechanisms and biological pathways involved in ROHHAD onset.

Through the ROHHAD IC, the work of each team collecting data in the field of each hypothesis (genetic, paraneoplastic ,autoimmune, epigenetic) will be better shared and discussed to enhance the quality of our respectively work and to allow better and faster international collaborations.

Contact

Dr Julie HARVENGT

CHU of Liège – Department of Human Genetics

Av de L’Hopital 1 , 4000 Liège, Belgium

Julie.Harvengt {at} chuliege.be

Secretariat:

Phone number +32 4 366 8145

genetique.humaine {at} chuliege.be