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Genes Modulating the Severity of Aortic Aneurysms (MSF1-TGFBR2) (MSF1-TGFBR2)

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ClinicalTrials.gov Identifier: NCT05146375
Recruitment Status : Recruiting
First Posted : December 6, 2021
Last Update Posted : January 13, 2023
Sponsor:
Collaborators:
Fédération Française de Cardiologie
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
French Cardiology Society

Study Description
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Brief Summary:

This project concerns a population at risk of sudden death by dissection of the thoracic aorta. Its interest is to make it possible to recognize the genes that protect or worsen the evolution of aneurysms, to better understand the mechanisms involved, to detect and treat aneurysms of the thoracic aorta, wich is a pathology that is completely silent clinically until life-threatening complications.

The variability in the severity of the disease within the same family is related to modifier genes.

The objective is to find the modifying factors that account for the variability in the severity of the progression of aneurysms of the thoracic aorta.


Condition or disease Intervention/treatment
Thoracic Aortic Aneurysm Biological: TGFBR2

Detailed Description:

Thoracic aortic aneurysms are silent, asymptomatic, potentially fatal pathologies due to the risk of aortic dissection. More and more often they are found during imaging tests done for another reason. Some aneurysms have genetic origin (autosomal dominantly inherited) and are particularly interesting because they can be recognized early (due to possible family screening), which allows us to understand the natural history of this pathology. The discovery of genes whose mutations explain the occurrence of these family aneurysms (initiator gene) has also made it possible to improve family screening and to better understand the pathophysiology of these aneurysms: we now recognize 3 groups of genes involved (extracellular matrix, contractile proteins of smooth muscle cell, TGF-β pathway (Transforming Growth Factor) [including mutations in TGF-β receptor 2 gene, TGFBR2]).

The variability in the severity of signs and aortic involvement is particularly marked in patients with aortic aneurysms due to mutations in the TGFBR2 gene. Some patients with these mutations present aggressive aneurysms with early dissection. Other patients have isolated late-onset aneurysms, and others have no signs.

This variability generates problems for clinical practice to give appropriate genetic advice, but also to adapt imaging monitoring, therapy, or sports restriction.

The present protocol aims is to investigate the variability in the severity of the disease within a large family carrying a mutation in the TGFBR2 gene. The MFS1 family is a family in which the aortic pathology is due to a mutation in the TGFBR2 gene. All patients with this family carry the same TGFBR2 mutation, heterozygous.

Study Design
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Study Type : Observational
Estimated Enrollment : 53 participants
Observational Model: Family-Based
Time Perspective: Prospective
Official Title: Genes Modulating the Severity of Aortic Aneurysms (MSF1-TGFBR2)
Actual Study Start Date : November 24, 2022
Estimated Primary Completion Date : November 30, 2023
Estimated Study Completion Date : November 30, 2025

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
MSF1
Each member of the MSF1 family who consents to participate to the study will be included.
 Biological: TGFBR2

TGFBR2 mutation correlation with severity of the aortic disease. Blood sampling. Serum will be analysed by DNA sequencing to detect specific mutations involved in aneurysms.

Cutaneous biopsy. Fibroblast culture will be done to assess the transcriptome analysis.


Outcome Measures
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Primary Outcome Measures :
  1. Clinical phenotype [ Time Frame: day 1 ]
    The criterion of severity of aortic disorder is based on the maximal aortic diameter measurement (in millimeter, measured at the level of the sinuses of Valsalva) and on age-adjusted aortic dilation.


Secondary Outcome Measures :
  1. TGFBR2 and other gene mutations involved in aneurysms [ Time Frame: All samples will be analysed at the same time, at the end of the recruitment. ]
    correlation genotype/phenotype

  2. Genotype analysis [ Time Frame: All samples will be analysed at the same time, at the end of the recruitment. ]
    Comparison between worst phenotype and genotype / Comparison between best phenotype and genotype

  3. Transcriptome analysis [ Time Frame: All samples will be analysed at the same time, at the end of the recruitment. ]
    Gene expression will be assessed by RNA-sequencing. Correlation between transcriptional profiles and clinical phenotype will be performed.


Biospecimen Retention:   Samples With DNA
blood sample (serum)

Eligibility Criteria
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Ages Eligible for Study:   10 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
53 members of the MFS1 family are currently identified and have a medical follow-up in the national referral center for Marfan syndrome of the hospital Bichat-Claude Bernard, Paris.
Criteria

Inclusion Criteria:

Member of MSF1 family. The MFS1 family is a family in which the aortic pathology is due to a mutation in the TGFBR2 gene. All patients with this family carry the same TGFBR2 mutation (heterozygous)

Exclusion Criteria:

Refusal or linguistic or psychological inability to sign informed consent

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05146375


Contacts
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Contact: Tessa BERGOT +33144907033 tessa.bergot@sfcardio.fr

Locations
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France
Hopital Bichat-Claude Bernard Recruiting
Paris, France
Contact: Guillaume JONDEAU, MD         
Sponsors and Collaborators
French Cardiology Society
Fédération Française de Cardiologie
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
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Principal Investigator: Guillaume JONDEAU, MD Hopital Bichat-Claude Bernard
More Information
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Responsible Party: French Cardiology Society
ClinicalTrials.gov Identifier: NCT05146375    
Other Study ID Numbers: 2021-02
First Posted: December 6, 2021    Key Record Dates
Last Update Posted: January 13, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by French Cardiology Society:
Vascular Diseases, Aneurysm
TGFBR2 mutation
Additional relevant MeSH terms:
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Aneurysm
Aortic Aneurysm
Aortic Aneurysm, Thoracic
 Vascular Diseases
Cardiovascular Diseases
Aortic Diseases