Genome-wide Epistasis for Cardiovascular Severity in Marfan Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Molecular characterization of the assembled 25% extreme ends cohort (UMC and AMC).
研究概览
简要总结
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic manifestations in the ocular, skeletal and cardiovascular systems. Morbidity and mortality are mostly determined by aortic root aneurysm dissection and rupture. Although mutations in FBN1, the gene coding for the extracellular matrix protein fibrillin-1, are the well-established genetic cause of this condition, there is a very poor correlation between the nature or location of the causal FBN1 mutation and the phenotypical outcome. Indeed, wide intra- and interfamilial phenotypical variability is observed. So, even with an identical primary mutation in all family members, the clinical spectrum varies widely, from completely asymptomatic to sudden death due to aortic dissection at a young age. The precise mechanisms underlying this variability remain largely elusive.
Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, we have carefully selected different innovative strategies to discover mother nature's own modifying capabilities with respect to Marfan syndrome aortopathy.
详细描述
In this project we will focus on the cardiovascular, or more specific, the TAAD (Thoracal Aorta Aneurysma Dissection) expressivity of the Marfan syndrome. The most frequent mutations in FBN1 (fibrilin-1 ), with significant aortopathy expressivity is p.Ile2585Thr; c.7754T>C and p.Ala882Val; c.2645C>T). We will limit the used population to p.Ile2585Thr; c.7754T>C mutation since this is the biggest population.
Marfan syndrome subjects carrying an identical FBN1 mutation show a variable aortopathy expressivity, even within one family. We hypothesize that the cardiovascular phenotypical variability is under control of genetic modifiers.
The first approach strategy involves ranking of carriers of the specific FBN1 mutation that present with significant variable aortopathy expressivity according to the severity of aortic aneurysma disease (based on Z-score, timing of surgery and manual expert curation). We will stratify these mutation carrying individuals in three groups: mild or no aortic disease (UMC, unaffected mutation carrier)), severely affected (AMC, affected mutation carrier), and participants with indeterminate data.
The second approach is the molecular characterisation of the 25% extreme cohort (AMC and UMC) using WGS (Whole Genome Sequencing) and linkage analysis.
Finally subjects peripheral blood mononuclear cells (PBMCs) of 10 severely affected mutation carrier (AMC) and 10 unaffected mutation carriers (UMC) as well as 2 controls will be reprogrammed to iPSCs (induced Pluripotential Stem Cells). These cells will finally be differentiated into VSMC's (VasculairSmoth Muscle Cells). The genomic integrity and identity of the iPSCs and the VSMCs will be validated using RT-PCR and immunocytochemistry.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with proven mutation (p.Ile2585Thr;c.7754C>T) in the FBN1 gene
排除标准
- 未提供
结局指标
主要结局
Molecular characterization of the assembled 25% extreme ends cohort (UMC and AMC).
时间窗: September 2023
Whole Genome Sequencing (WGS) and linkage analysis will be used for this purpose
次要结局
- Omics integration for modifier identification in the 5% extreme ends of the cohort (UMC and AMC)(September 2023)
- Functional validation of the modifiers.(2024)
- Replication of the identified modifiers in a large MFS cohort Time frame: December 2024(2024)