Diagnosis of RSTS: Identification of the Acetylation Profiles as Epigenetic Markers for Assessing Causality of CREBBP and EP300 Variants.

NCT04122742 | Unknown

• 1 other identifier: CHUBX 2019/19
• Study Type: observational
• Target: 154
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Rubinstein-Taybi Syndrome

Keywords

Epigenetics; Acetylation; Diagnostic; Induced pluripotent stem cells; Rubinstein-Taybi syndrome

Outcome Measures

Primary Outcomes (1)

• 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

  Inclusion visit

Secondary Outcomes (2)

• Identification of different target genes between SRT patients and controls

  Inclusion visit

• Evidence of a significantly different level of expression for common target genes for RSTS patients and controls

  Inclusion visit

Study Arms (1)

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

Interventions

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

Performed with a 3 mm diameter punch under local anesthesia. The procedure can be done in a consultation office respecting a strict asepsis.

Patients with RSTS

Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsy OTHER

induced Pluripotent Stem Cells (iPSC) production of patients with CREBBP mutation and differentiation into cortical neurons and pyramidal neurons

Patients with RSTS

Histone acetylation profiles of cells of SRT patients with CREBBP mutations OTHER

Study of acetylome by liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS) Validation of specific acetylation targets by ChIP-Sequencing

Patients with RSTS

Functional involvement of identified epigenetic alterations OTHER

Transcriptome analysis with RNA-Seq Generation of isogenic iPSC clones by correction of CREBBP mutations in SRT patients by CrispR-Cas9.

Patients with RSTS

Culture of lymphoblastoid line from blood sample BIOLOGICAL

Achievement of a ficoll Culture of lymphoblasts and conservation Establishment of lymphoblastoid line and conservation

Patients with RSTS

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patient with a clinical and molecular diagnosis of RSTS having a specialized consultation in CHU de Bordeaux

You may qualify if:

• 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

You may not qualify if:

• 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:
• by histone deacetylase inhibitor (sodium valproate) likely to interfere with the interpretation of the results.

Sponsors & Collaborators

• University Hospital, Bordeaux: lead

Study Sites (1)

Centre Hospitalier Universitaire de Bordeaux

Talence, 33400, France

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

skin biopsy and whole blood sample

MeSH Terms

Conditions

Rubinstein-Taybi Syndrome; Disease

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Dysostoses; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Central Study Contacts

Julien VAN-GILS

CONTACT

+33 5 57 82 03 53; julien.van-gils@chu-bordeaux.fr

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2019
• First Posted: October 10, 2019
• Study Start: October 8, 2019
• Primary Completion: October 1, 2025
• Study Completion: October 1, 2025
• Last Updated: January 17, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)