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

Thoracic Aortic Aneurysm Clinical Trial

— MSF1-TGFBR2  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05146375
• Other study ID #: 2021-02
• Status: Active, not recruiting
• Start date: November 24, 2022
• Est. completion date: November 30, 2025

Study information

• Verified date: March 2024
• Source: French Cardiology Society
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 17
• Est. completion date: November 30, 2025
• Est. primary completion date: September 28, 2023
• Gender: All
• Age group: 10 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aneurysm
• Aortic Aneurysm
• Aortic Aneurysm, Thoracic
• Thoracic Aortic Aneurysm

Intervention

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.

Locations

Country	Name	City	State
France	Hopital Bichat-Claude Bernard	Paris

Sponsors (3)

Lead Sponsor	Collaborator
French Cardiology Society	Fédération Française de Cardiologie, Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical phenotype	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.	day 1
Secondary	TGFBR2 and other gene mutations involved in aneurysms	correlation genotype/phenotype	All samples will be analysed at the same time, at the end of the recruitment.
Secondary	Genotype analysis	Comparison between worst phenotype and genotype / Comparison between best phenotype and genotype	All samples will be analysed at the same time, at the end of the recruitment.
Secondary	Transcriptome analysis	Gene expression will be assessed by RNA-sequencing. Correlation between transcriptional profiles and clinical phenotype will be performed.	All samples will be analysed at the same time, at the end of the recruitment.