Rubinstein-Taybi SyndromeGENEPINCT04122742
Diagnosis of RSTS: Identification of the Acetylation Profiles as Epigenetic Markers for Assessing Causality of CREBBP and EP300 Variants.
An observational study of Rubinstein-Taybi Syndrome, run by University Hospital, Bordeaux at 1 site in France.
Trial summary
Rubinstein-Taybi syndrome (RSTS) is a rare and severe congenital developmental disorder characterized by congenital anomalies and intellectual disability with a long term memory deficit. The main challenge is to improve the intellectual and memory efficiency of these patients. Read more about this study
- Who is it for?
- Ages 2 years and older
- Conditions the study is for
- Rubinstein-Taybi Syndrome
- What is being tested?
- skin biopsy for the primary fibroblast culture and a 15 ml blood sample (3 unnamed samples of 5ml) in each of the 4 SRT patients included., Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsy and Histone acetylation profiles of cells of SRT patients with CREBBP mutations
- Type of treatment
- Surgery or procedure
- How many people
- 154 participants
- Where
- 1 siteFrance
- Study dates
- 8 Oct 2019to Oct 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Patient with a clinical and molecular diagnosis of RSTS having a specialized consultation in CHU de Bordeaux
Who may be able to join
- Patient with a clinical and molecular diagnosis of RSTS
- Patients carrying the CREBBP or EP300 variants
- Patients older than 2 years
- Affiliated patients or beneficiaries of a social security scheme.
- Free, informed and signed consent by the parents or holder of parental authority for minor patients
- Free, informed and signed consent by the patient representative for the major patients under guardianship
- Free, informed and signed consent by the patient for major patients
Who cannot join
- Patients having:
- a history of allergy to any product or device that may be used before, during, and after the biopsy;
- cutaneous disease of the areas where the biopsy is to be performed
- underwent physical treatment (radiotherapy, ...) on the area to be biopsied, during the last 6 months
- hereditary or acquired disorders of hemostasis
- Patients under treatment:
- likely to act on the haemostasis (anticoagulants, platelet antiaggregants, ...) in the month preceding the inclusion and during the study
- by histone deacetylase inhibitor (sodium valproate) likely to interfere with the interpretation of the results.
Trial locations and contacts
1 site in 1 country.
France1 site, 1 recruiting
- Recruiting
Centre Hospitalier Universitaire de Bordeaux
Talence, 33400
Julien VAN-GILS, +33 5 57 82 03 53, julien.van-gils@chu-bordeaux.fr
About this study
Rubinstein-Taybi syndrome (RSTS) is a rare and severe congenital developmental disorder characterized by congenital anomalies and intellectual disability with a long term memory deficit. The main challenge is to improve the intellectual and memory efficiency of these patients. CREBBP and EP300 are the two genes known to cause RSTS. Both paralogs play a major role in chromatin remodeling and encode for transcriptional co-activators interacting with many proteins.
The aim of this pilot study is to characterize the histone acetylation profiles in order to identify specific acetylation markers during normal and pathological neuronal differentiation of cortical and pyramidal neurons in RSTS.
Read the detailed description
CREBBP and EP300 are the two paralog genes associated with RSTS determinism and code for CBP and p300, respectively. These proteins are transcriptional coactivators that possess a catalytic lysine acetyl transferase (KAT) domain involved in the acetylation of lysine residues of histones but also other proteins. CBP and p300 promote transcription by creating a chromatin environment that is favorable for gene expression and by linking different transcription factors to each other. They thus orchestrate the regulation of the transcription machinery, from the basal promoter to the enhancers of the target genes.
RSTS is considered a genetic model of neurodevelopmental anomaly with an epigenetic component.
Histone acetylation is one of the major post-translational modifications (PTMs) of these proteins that provide for the formation and control of chromatin structure. When differentiating embryonic cells, this modification plays a key role in transcriptional activation.
The mouse models of RSTS have made the link between the modulation of histone acetylation and the formation of memory by showing their key role in neuronal plasticity. However no data exists on the acetylation of histones in the neurons of RSTS patients. Furthermore, in humans, the molecular pathways impacted by these alterations during neurodevelopment are not specified, especially in the pyramidal neurons which are the precursors of hippocampal neurons involved in the encoding and storage of memory.
In RSTS a loss of CBP function results in a deficit in KAT activity, which is responsible for altering histone acetylation, leading to inappropriate changes in chromatin structure. The consequence of a mutation is a result of a deregulation of the activity of genes involved in development. No neuronal level studies are currently available on the functional link between histone acetylation and deregulated genes in the RSTS.
In this project, investigators will identify target genes whose epigenetic regulation is mediated by histone acetylation. More specifically, the study will focus on chromatin dynamics during normal and pathological neuronal differentiation of cortical and pyramidal neurons. Investigators will determine among the CBP-dependent histone markers, those that are modified in RSTS patients cells and the loci they control. In parallel, investigators will define genes whose neuronal expression is altered in RSTS patients.
The integration of all these data will allow us to specify which genes are deregulated during neuronal differentiation as a consequence of CBP lysine acetyltransferase function loss.
- Conditions
- Rubinstein-Taybi Syndrome
- Being tested
- skin biopsy for the primary fibroblast culture and a 15 ml blood sample (3 unnamed samples of 5ml) in each of the 4 SRT patients included., Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsy, Histone acetylation profiles of cells of SRT patients with CREBBP mutations, Functional involvement of identified epigenetic alterations, Culture of lymphoblastoid line from blood sample
- Keywords
- Epigenetics, Acetylation, Diagnostic, Induced pluripotent stem cells, Rubinstein-Taybi syndrome
- Medical subject headings
- Rubinstein-Taybi Syndrome, Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
skin biopsy for the primary fibroblast culture and a 15 ml blood sample (3 unnamed samples of 5ml) in each of the 4 SRT patients included.Procedure or surgery
Performed with a 3 mm diameter punch under local anesthesia. The procedure can be done in a consultation office respecting a strict asepsis.
Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsyOther
induced Pluripotent Stem Cells (iPSC) production of patients with CREBBP mutation and differentiation into cortical neurons and pyramidal neurons
Histone acetylation profiles of cells of SRT patients with CREBBP mutationsOther
Study of acetylome by liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS) Validation of specific acetylation targets by ChIP-Sequencing
Functional involvement of identified epigenetic alterationsOther
Transcriptome analysis with RNA-Seq Generation of isogenic iPSC clones by correction of CREBBP mutations in SRT patients by CrispR-Cas9.
Culture of lymphoblastoid line from blood sampleBiological
Achievement of a ficoll Culture of lymphoblasts and conservation Establishment of lymphoblastoid line and conservation
| Study group | Role | What they receive |
|---|---|---|
| Patients with RSTS | Not described Receives: Procedure: skin biopsy for the primary fibroblast culture and a 15 ml blood sample (3 unnamed samples of 5ml) in each of the 4 SRT patients included.; Other: Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsy; Other: Histone acetylation profiles of cells of SRT patients with CREBBP mutations; Other: Functional involvement of identified epigenetic alterations; Biological: Culture of lymphoblastoid line from blood sample |
What is being measured
The primary outcome is the main question the study is designed to answer.
Identification of a specific acetylation profile of RSTS
From skin biopsy sample collected at inclusion visit :
- No assumptions about the number of histone marks needed to define the profile
- Will be retained as the specific mark of the disease if it is 100% present in the cases and 100% absent in the controls
- The specific profile can be defined in one or more stages of cell differentiation: iPSC - neuronal progenitor - cortical and pyramidal neurons
Measured: Inclusion visit
Secondary outcomes (2)
Identification of different target genes between SRT patients and controls
SRT patients will be compared to 4 control cell cultures from healthy volunteers matched for age and sex already available
Measured: Inclusion visit
Evidence of a significantly different level of expression for common target genes for RSTS patients and controls
Measured: Inclusion visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Oct 2019
- Study start8 Oct 2019
- Primary completionOct 2025 (estimated)
- Study completionOct 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Rubinstein-Taybi SyndromeStudies of the same condition, open and under way.
- More trials run by University Hospital, BordeauxThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 154 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Bordeaux
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04122742
- Sponsor's protocol ID
- CHUBX 2019/19
- Acronym
- GENEPI
- Status last verified
- Jan 2024
- First submitted
- 9 Oct 2019
- Last updated
- 17 Jan 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Diagnosis of RSTS: Identification of the Acetylation Profiles as Epigenetic Markers for Assessing Causality of CREBBP and EP300 Variants.
- ClinicalTrials.gov ID
- NCT04122742
- Acronym / sponsor ID
- GENEPI / CHUBX 2019/19
- Conditions
- Rubinstein-Taybi Syndrome
- Keywords
- Epigenetics, Acetylation, Diagnostic, Induced pluripotent stem cells, Rubinstein-Taybi syndrome
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 154 participants (estimated)
- Lead sponsor
- University Hospital, BordeauxUniversity, hospital or other
- Study start
- 8 Oct 2019 (actual)
- Primary completion
- Oct 2025 (estimated)
- Study completion
- Oct 2025 (estimated)
- First posted
- 10 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Rubinstein-Taybi syndrome (RSTS) is a rare and severe congenital developmental disorder characterized by congenital anomalies and intellectual disability with a long term memory deficit. The main challenge is to improve the intellectual and memory efficiency of these patients. CREBBP and EP300 are the two genes known to cause RSTS. Both paralogs play a major role in chromatin remodeling and encode for transcriptional co-activators interacting with many proteins.
The aim of this pilot study is to characterize the histone acetylation profiles in order to identify specific acetylation markers during normal and pathological neuronal differentiation of cortical and pyramidal neurons in RSTS.
Detailed description
CREBBP and EP300 are the two paralog genes associated with RSTS determinism and code for CBP and p300, respectively. These proteins are transcriptional coactivators that possess a catalytic lysine acetyl transferase (KAT) domain involved in the acetylation of lysine residues of histones but also other proteins. CBP and p300 promote transcription by creating a chromatin environment that is favorable for gene expression and by linking different transcription factors to each other. They thus orchestrate the regulation of the transcription machinery, from the basal promoter to the enhancers of the target genes.
RSTS is considered a genetic model of neurodevelopmental anomaly with an epigenetic component.
Histone acetylation is one of the major post-translational modifications (PTMs) of these proteins that provide for the formation and control of chromatin structure. When differentiating embryonic cells, this modification plays a key role in transcriptional activation.
The mouse models of RSTS have made the link between the modulation of histone acetylation and the formation of memory by showing their key role in neuronal plasticity. However no data exists on the acetylation of histones in the neurons of RSTS patients. Furthermore, in humans, the molecular pathways impacted by these alterations during neurodevelopment are not specified, especially in the pyramidal neurons which are the precursors of hippocampal neurons involved in the encoding and storage of memory.
In RSTS a loss of CBP function results in a deficit in KAT activity, which is responsible for altering histone acetylation, leading to inappropriate changes in chromatin structure. The consequence of a mutation is a result of a deregulation of the activity of genes involved in development. No neuronal level studies are currently available on the functional link between histone acetylation and deregulated genes in the RSTS.
In this project, investigators will identify target genes whose epigenetic regulation is mediated by histone acetylation. More specifically, the study will focus on chromatin dynamics during normal and pathological neuronal differentiation of cortical and pyramidal neurons. Investigators will determine among the CBP-dependent histone markers, those that are modified in RSTS patients cells and the loci they control. In parallel, investigators will define genes whose neuronal expression is altered in RSTS patients.
The integration of all these data will allow us to specify which genes are deregulated during neuronal differentiation as a consequence of CBP lysine acetyltransferase function loss.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with RSTS | – | Procedure: skin biopsy for the primary fibroblast culture and a 15 ml blood sample (3 unnamed samples of 5ml) in each of the 4 SRT patients included., Other: Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsy, Other: Histone acetylation profiles of cells of SRT patients with CREBBP mutations, Other: Functional involvement of identified epigenetic alterations, Biological: Culture of lymphoblastoid line from blood sample |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patient with a clinical and molecular diagnosis of RSTS having a specialized consultation in CHU de Bordeaux
Key inclusion criteria (7 listed)
- Patient with a clinical and molecular diagnosis of RSTS
- Patients carrying the CREBBP or EP300 variants
- Patients older than 2 years
- Affiliated patients or beneficiaries of a social security scheme.
- Free, informed and signed consent by the parents or holder of parental authority for minor patients
Key exclusion criteria (8 listed)
- a history of allergy to any product or device that may be used before, during, and after the biopsy;
- cutaneous disease of the areas where the biopsy is to be performed
- underwent physical treatment (radiotherapy, ...) on the area to be biopsied, during the last 6 months
- hereditary or acquired disorders of hemostasis
- likely to act on the haemostasis (anticoagulants, platelet antiaggregants, ...) in the month preceding the inclusion and during the study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| skin biopsy for the primary fibroblast culture and a 15 ml blood sample (3 unnamed samples of 5ml) in each of the 4 SRT patients included.Performed with a 3 mm diameter punch under local anesthesia. The procedure can be done in a consultation office respecting a strict asepsis. | Procedure or surgery | Patients with RSTS |
| Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsyinduced Pluripotent Stem Cells (iPSC) production of patients with CREBBP mutation and differentiation into cortical neurons and pyramidal neurons | Other | Patients with RSTS |
| Histone acetylation profiles of cells of SRT patients with CREBBP mutationsStudy of acetylome by liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS) Validation of specific acetylation targets by ChIP-Sequencing | Other | Patients with RSTS |
| Functional involvement of identified epigenetic alterationsTranscriptome analysis with RNA-Seq Generation of isogenic iPSC clones by correction of CREBBP mutations in SRT patients by CrispR-Cas9. | Other | Patients with RSTS |
| Culture of lymphoblastoid line from blood sampleAchievement of a ficoll Culture of lymphoblasts and conservation Establishment of lymphoblastoid line and conservation | Biological | Patients with RSTS |
Primary outcome
Identification of a specific acetylation profile of RSTS
Time frame: Inclusion visit
From skin biopsy sample collected at inclusion visit : * No assumptions about the number of histone marks needed to define the profile * Will be retained as the specific mark of the disease if it is 100% present in the cases and 100% absent in the controls * The specific profile can be defined in one or more stages of cell differentiation: iPSC - neuronal progenitor - cortical and pyramidal neurons
2 secondary outcomes
Identification of different target genes between SRT patients and controls
Time frame: Inclusion visit
Evidence of a significantly different level of expression for common target genes for RSTS patients and controls
Time frame: Inclusion visit
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jan 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Rubinstein-Taybi Syndrome, run by University Hospital, Bordeaux at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 17 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Julien VAN-GILS (+33 5 57 82 03 53, julien.van-gils@chu-bordeaux.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identification of a specific acetylation profile of RSTS (time frame: Inclusion visit). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jan 2024.