Key result
Exome sequencing links variants across 8 modifier genes to aortic severity in Marfan syndrome.
Why the study?
Clinical course and aortic severity vary widely in Marfan syndrome even among patients sharing the same FBN1 variant, suggesting additional genetic modifiers influence the cardiovascular phenotype.
Observational (n=25)
Yes
Exome sequencing identified novel genetic variants in genes regulating the extracellular matrix and TGFβ pathways that may modify the severity of aortic aneurysms and dissections in Marfan Syndrome.
May support exome sequencing to stratify aortic risk in Marfan syndrome; leaves open validation and clinical utility in prospective studies.
Marfan Syndrome (MFS) is an autosomal dominant condition caused by variants in the fibrillin-1 (FBN1) gene. Cardinal features of MFS include ectopia lentis (EL), musculoskeletal features and aortic root aneurysm and dissection. Although dissection of the ascending aorta is the main cause of mortality in MFS, the clinical course differs considerably in age of onset and severity, even among individuals who share the same causative variant, suggesting the existence of additional genetic variants that modify the severity of the cardiovascular phenotype in MFS. We recruited MFS patients and classified them into severe (n = 8) or mild aortic phenotype (n = 14) according to age of presentation of the first aorta-related incident. We used Exome Sequencing to identify the genetic variants associated with the severity of aortic manifestations and we performed linkage analysis where suitable. We found five genes associated with severe aortic phenotype and three genes that could be protective for this phenotype in MFS. These genes regulate components of the extracellular matrix, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management and, potentially, therapies for these patients.
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Jimenez et al. (2022) conducted an observational in Marfan Syndrome (n=25). Genetic variants (Exome Sequencing) vs. Mild vs severe aortic phenotype was evaluated on Identification of candidate modifier genes associated with severe or mild aortic phenotype. Exome sequencing identified variants in five genes associated with a severe aortic phenotype and three genes associated with a mild, potentially protective, aortic phenotype in Marfan Syndrome.
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