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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Thoracic Aortic Aneurysm
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Actual): 17

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Hôpital Bichat-Claude Bernard

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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.
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.

Collaborators and Investigators

• Sponsor: French Cardiology Society
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; Fédération Française de Cardiologie
• Investigators: Principal Investigator: Guillaume JONDEAU, MD, Hôpital Bichat-Claude Bernard

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2022
• Primary Completion (Actual): September 28, 2023
• Study Completion (Estimated): November 30, 2025

Study Registration Dates

• First Submitted: November 23, 2021
• First Submitted That Met QC Criteria: November 23, 2021
• First Posted (Actual): December 6, 2021

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Vascular Diseases, Aneurysm; TGFBR2 mutation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Aortic Diseases; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Thoracic
• Other Study ID Numbers: 2021-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No