Taybi Linder SyndromeATACNCT06111950
Study of the Pathophysiology of RNU4ATAC and RTTN Associated Syndromes
A study testing Blood samples, Skin biopsies and Fetal samples in people with Taybi Linder Syndrome and Microcephalic Osteodysplastic Primordial Dwarfism Types I and III, run by Hospices Civils de Lyon at 6 sites in France.
Trial summary
In the human genome, about 750 genes contain one intron excised by the minor spliceosome. These genes are named U12 genes, and these introns, minor or U12 introns. The minor spliceosome comprises its own set of snRNAs, among which U4atac. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Taybi Linder Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism Types I and III, Roifman Syndrome
- What is being tested?
- Blood samples, Skin biopsies and Fetal samples
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 6 sitesFrance
- Study dates
- 27 Aug 2024to 27 Aug 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- TALS, RFMN, LWS or other pathology patients
- Woman or man
- All ages
- Presence of bi-allelic mutations of RNU4ATAC or RTTN
- Written consent of parents or legal guardian(s)
- Affiliation to a Social Security scheme
Show all 18Show fewer
- Healthy participants (Parent of the patient)
- Woman or man
- Major
- Presence of mono-allelic mutations of RNU4ATAC
- Written consent of the participant
- Affiliation to a Social Security scheme
- Parents having recourse to a medical termination of pregnancy or having had a spontaneous miscarriage (for fetus samples)
- Woman or man
- Major
- Presence of bi-allelic mutations of RNU4ATAC or RTTN in the fetus
- Written parental consent
- Affiliation to a Social Security scheme
Who cannot join
- Subject participating in another research including an exclusion period still in progress.
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
6 sites in 1 country
France6 sites, 6 recruiting
- Not yet recruiting
Centre de référence des anomalies du développement et syndromes malformatifs du Sud-Ouest Occitanie Réunion, CHU de Bordeaux-GH Pellegrin
Bordeaux, 33000
Didier LACOMBE, MD, PhD, 05 56 79 56 48 ext. +33, didier.lacombe@chu-bordeaux.fr
- Recruiting
Centre de référence anomalies du développement de Lyon, Hôpital Femme Mère Enfant
Bron, 69500
Patrick EDERY, MD, PhD, 04 72 12 96 98, charles-patrick.edery@chu-lyon.fr
- Not yet recruiting
Centre de référence des anomalies du développement et syndromes malformatifs de l'Est, CHU de DIJON
Dijon, 9000
Laurence OLIVIER-FAIVRE, MD, PhD, 03 80 29 53 13 ext. +33, laurence.faivre@chu-dijon.fr
- Not yet recruiting
Centre de référence des anomalies du développement et syndromes malformatifs de l'inter région Nord-Ouest, Hôpital J de Flandre
Lille, 59000
Sylvie MANOUVRIER-HANU, MD, PhD, 03 20 44 49 11 ext. +33, sylvie.manouvrier@chru-lille.fr
- Not yet recruiting
Unité Fonctionelle d'embryo-fœtopathologie, Hôpital Necker-Enfants Malades
Paris, 75743
Tania ATTIE-BITTACH, MD, PhD, 01 44 49 51 44 ext. +33, tania.attie@inserm.fr
- Not yet recruiting
Centre de référence des anomalies du développement et syndromes malformatifs de l'Ouest, Hôpital Sud
Rennes, 35000
Sylvie ODENT, MD, PhD, 02 99 26 67 44 ext. +33, sylvie.odent@chru-rennes.fr
About this study
Official title: Study of the Consequences of Mutations of the RNU4ATAC and RTTN Genes by Transcriptomic, Biochemical and Cellular Approaches in Order to Determine the Pathophysiology of Their Associated Syndromes: Microcephalic Osteodysplastic Primordial Dwarfism Type I/III, Roifman Syndrome and Lowry-Wood Syndrome
In the human genome, about 750 genes contain one intron excised by the minor spliceosome. These genes are named U12 genes, and these introns, minor or U12 introns. The minor spliceosome comprises its own set of snRNAs, among which U4atac. Its non-coding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS), Roifman (RFMN) and Lowry-Wood syndromes (LWS). These rare developmental disorders associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy and immunodeficiency. Their physiopathological mechanisms remain unsolved: the number of U12 genes involved, their identity and function, or the cellular mechanisms impacted by the splicing defect, are still unknown.
The hypothesis of the study is that U12 genes coding for primary cilia components are particularly sensitive to minor splicing defects caused by RNU4ATAC mutations. Indeed, a child showing signs of TALS but negative for RNU4ATAC was found to carry a homozygous variant in the RTTN gene, coding for the rotatin protein located at the centrosome and the base of the primary cilia and playing a role in maintaining these structures. In addition, bi-allelic RNU4ATAC mutations were identified in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS.
To better understand the causes of these pathologies, a cohort of patients with syndromes associated with bi-allele mutations of the RNU4ATAC or RTTN gene will be gathered, in order to conduct studies on the cells of these patients. Blood samples will be taken, as well as skin biopsies, if possible. These samples will be used to create induced pluripotent stem cell lines. Blood samples will also be collected from the parents of RNU4ATAC patients, to eliminate in transcriptomic analyses expression variations due to differences in genetic background. Biopsies of skin, muscle and brain tissue will be collected on foetuses carrying two-allele RNU4ATAC or RTTN mutations whose parents have had a miscarriage or have chosen to have a medical abortion. The biological samples collected will be used to study the transcription level of U12 genes, the splicing of their pre-messenger RNA, their main cellular functions, and the structural characteristics of tissues and cells.
- Conditions
- Taybi Linder Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism Types I and III, Roifman Syndrome, Lowry Wood Syndrome
- Being tested
- Blood samples, Skin biopsies, Fetal samples
- Keywords
- Genetic diseases, Splicing, Minor introns, U4atac, Primary cillium
- Medical subject headings
- Microcephalic osteodysplastic primordial dwarfism, type 1, Roifman syndrome, Lowry Wood syndrome, Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood samplesOther
Blood samples of 5 ml to 15 ml depending on their weight
Skin biopsiesOther
Biopsies of fragment of skin 2 to 3 mm long by 1 mm wide and 1 mm deep will preferably be taken on the inside of the arm, in the upper third, between the bend of the elbow and the hollow of the armpit under strict sterility conditions.
Fetal samplesOther
Skin, muscle, brain and bone biopsies will be collected from fetuses in the autopsy room after the medical termination of pregnancy or miscarriage
| Study group | Role | What they receive |
|---|---|---|
| RNU4ATAC patient | Other | Patient with bi-allelic mutation of the RNU4ATAC gene Receives: Other: Blood samples; Other: Skin biopsies |
| RNU4ATAC fetus | Other | Fetus with bi-allelic mutation of the RNU4ATAC gene Receives: Other: Fetal samples |
| RNU4ATAC parent | Other | Parent of patient or fetus with bi-allelic mutation of the RNU4ATAC gene and who present themselve mono-allelic mutation of the RNU4ATAC gene Receives: Other: Blood samples |
| RTTN patient | Other | Patient with bi-allelic mutation of the RTTN gene Receives: Other: Blood samples; Other: Skin biopsies |
| RTTN fetus | Other | Fetus with bi-allelic mutation of the RTTN gene Receives: Other: Fetal samples |
What is being measured
The primary outcome is the main question the study is designed to answer.
Identification of RNU4ATAC mutations consequences at the cellular level
The dysfunctions present in the different cell types obtained from RNU4ATAC patients will be identified by comparison with the controls, and will be compared with those present in RTTN patients.
Consequences in cells of patients of RNU4ATAC mutations on the length and the structure of the primary cilium, as measured by fluorescence microscopy, and on the formation of small nuclear ribonucleoprotein (snRNPs) particles, as measured by glycerol gradient sedimentation analysis
Measured: 5 years
Secondary outcomes (2)
Minor splicing anomalies
The number and list of U12 genes for which an alteration of splicing will be identified in patient cells relatively to control cells will be compared, taking into account the different phenotypes (TALS, RFMN, LWS and other pathologies possibly identified).
Consequences in cells of patients of RNU4ATAC mutations on minor intron splicing, as measured by intron retention analysis with the IRFinder and KisSplice bioinformatics softwares following RNA-sequencing experiments
Measured: 5 years
Understanding of neuronal differentiation anomalies
Abnormalities in the behaviour of cells differentiated into neuronal progenitors will be identified by comparison with the controls, and will be compared taking into account the different phenotypes (TALS, RFMN, LWS and other pathology(s)) possibly identified).
Consequences of RNU4ATAC mutations on the ability of induced pluripotent stem cells to differentiate towards the neuronal lineage, as measured by immunocytochemistry
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Nov 2023
- Study start27 Aug 2024
- Primary completion27 Aug 2029 (estimated)
- Study completion27 Aug 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Taybi Linder SyndromeStudies of the same condition, open and under way.
- More trials run by Hospices Civils de LyonThe 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
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 45 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospices Civils de Lyon
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06111950
- Sponsor's protocol ID
- 69HCL20_0599
- Acronym
- ATAC
- Status last verified
- Oct 2024
- First submitted
- 31 Mar 2023
- Last updated
- 9 Oct 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 9 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Study of the Consequences of Mutations of the RNU4ATAC and RTTN Genes by Transcriptomic, Biochemical and Cellular Approaches in Order to Determine the Pathophysiology of Their Associated Syndromes: Microcephalic Osteodysplastic Primordial Dwarfism Type I/III, Roifman Syndrome and Lowry-Wood Syndrome
- ClinicalTrials.gov ID
- NCT06111950
- Acronym / sponsor ID
- ATAC / 69HCL20_0599
- Conditions
- Taybi Linder Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism Types I and III, Roifman Syndrome, Lowry Wood Syndrome
- Keywords
- Genetic diseases, Splicing, Minor introns, U4atac, Primary cillium
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 45 participants (estimated)
- Lead sponsor
- Hospices Civils de LyonUniversity, hospital or other
- Study start
- 27 Aug 2024 (actual)
- Primary completion
- 27 Aug 2029 (estimated)
- Study completion
- 27 Aug 2029 (estimated)
- First posted
- 1 Nov 2023 (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.
In the human genome, about 750 genes contain one intron excised by the minor spliceosome. These genes are named U12 genes, and these introns, minor or U12 introns. The minor spliceosome comprises its own set of snRNAs, among which U4atac. Its non-coding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS), Roifman (RFMN) and Lowry-Wood syndromes (LWS). These rare developmental disorders associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy and immunodeficiency. Their physiopathological mechanisms remain unsolved: the number of U12 genes involved, their identity and function, or the cellular mechanisms impacted by the splicing defect, are still unknown.
The hypothesis of the study is that U12 genes coding for primary cilia components are particularly sensitive to minor splicing defects caused by RNU4ATAC mutations. Indeed, a child showing signs of TALS but negative for RNU4ATAC was found to carry a homozygous variant in the RTTN gene, coding for the rotatin protein located at the centrosome and the base of the primary cilia and playing a role in maintaining these structures. In addition, bi-allelic RNU4ATAC mutations were identified in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS.
To better understand the causes of these pathologies, a cohort of patients with syndromes associated with bi-allele mutations of the RNU4ATAC or RTTN gene will be gathered, in order to conduct studies on the cells of these patients. Blood samples will be taken, as well as skin biopsies, if possible. These samples will be used to create induced pluripotent stem cell lines. Blood samples will also be collected from the parents of RNU4ATAC patients, to eliminate in transcriptomic analyses expression variations due to differences in genetic background. Biopsies of skin, muscle and brain tissue will be collected on foetuses carrying two-allele RNU4ATAC or RTTN mutations whose parents have had a miscarriage or have chosen to have a medical abortion. The biological samples collected will be used to study the transcription level of U12 genes, the splicing of their pre-messenger RNA, their main cellular functions, and the structural characteristics of tissues and cells.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| RNU4ATAC patient | Other | Other: Blood samples, Other: Skin biopsiesPatient with bi-allelic mutation of the RNU4ATAC gene |
| RNU4ATAC fetus | Other | Other: Fetal samplesFetus with bi-allelic mutation of the RNU4ATAC gene |
| RNU4ATAC parent | Other | Other: Blood samplesParent of patient or fetus with bi-allelic mutation of the RNU4ATAC gene and who present themselve mono-allelic mutation of the RNU4ATAC gene |
| RTTN patient | Other | Other: Blood samples, Other: Skin biopsiesPatient with bi-allelic mutation of the RTTN gene |
| RTTN fetus | Other | Other: Fetal samplesFetus with bi-allelic mutation of the RTTN gene |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (18 listed)
- TALS, RFMN, LWS or other pathology patients
- Woman or man
- All ages
- Presence of bi-allelic mutations of RNU4ATAC or RTTN
- Written consent of parents or legal guardian(s)
Key exclusion criteria (1 listed)
- Subject participating in another research including an exclusion period still in progress.
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 |
|---|---|---|
| Blood samplesBlood samples of 5 ml to 15 ml depending on their weight | Other | RNU4ATAC parent, RNU4ATAC patient, RTTN patient |
| Skin biopsiesBiopsies of fragment of skin 2 to 3 mm long by 1 mm wide and 1 mm deep will preferably be taken on the inside of the arm, in the upper third, between the bend of the elbow and the hollow of the armpit under strict sterility conditions. | Other | RNU4ATAC patient, RTTN patient |
| Fetal samplesSkin, muscle, brain and bone biopsies will be collected from fetuses in the autopsy room after the medical termination of pregnancy or miscarriage | Other | RNU4ATAC fetus, RTTN fetus |
Primary outcome
Identification of RNU4ATAC mutations consequences at the cellular level
Time frame: 5 years
The dysfunctions present in the different cell types obtained from RNU4ATAC patients will be identified by comparison with the controls, and will be compared with those present in RTTN patients. Consequences in cells of patients of RNU4ATAC mutations on the length and the structure of the primary cilium, as measured by fluorescence microscopy, and on the formation of small nuclear ribonucleoprotein (snRNPs) particles, as measured by glycerol gradient sedimentation analysis
2 secondary outcomes
Minor splicing anomalies
Time frame: 5 years
Understanding of neuronal differentiation anomalies
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2024.
- Individual participant dataSharing planned: No
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.
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Blood samples, Skin biopsies and Fetal samples in people with Taybi Linder Syndrome and Microcephalic Osteodysplastic Primordial Dwarfism Types I and III, run by Hospices Civils de Lyon at 6 sites 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 18 inclusion and 1 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: looking for participants now, as of the sponsor's last update on 9 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sylvie MAZOYER, Dr (04 81 10 65 33 ext. +33, sylvie.mazoyer@inserm.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identification of RNU4ATAC mutations consequences at the cellular level (time frame: 5 years). 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 9 Oct 2024.