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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Thoracic Aortic Aneurysm

Intervention / Treatment
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* Biological: TGFBR2


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MSF1<br>Each member of the MSF1 family who consents to participate to the study will be included. | Biological: TGFBR2<br>* 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.<br>|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vascular Diseases, Aneurysm, TGFBR2 mutation