Marfan syndrome (MS) is a systemic disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the cardiovascular, musculoskeletal, ocular, and central nervous systems. Of particular concern is the risk for the development of a life threatening, aortic aneurysm or dissection. The syndrome shows autosomal dominant inheritance (only one copy of a mutation is necessary for expression of disease) and complete penetrance, but is notable for variability in the age of onset, tissue distribution, and severity of clinical manifestations, both between and within affected families. Because mutations are heterogeneous and approximately 30% of MS cases are due to de novo mutations, direct testing often requires complete gene analysis. Mutations in fibrillin-1 (FBN1) have been firmly established as a cause of MS, as well as other conditions such as familial ectopia lentis, and in families with an inherited form of aortic aneurysms. Defects in the gene that encodes fibrillin-1, the main structural component of the elastinassociated microfibrils, are responsible for these disorders. Mutations in the FBN1 gene are detected in approximately 80% and 40% of patients that meet and do not meet Ghent diagnostic criteria for MS, respectively.
Recently, Mizuguchi et al. found a strong association between mutations in the Transforming Growth Factor ß Receptor 2 gene (TGFBR2) and MS1. In their study, they reported 4 mutations (1 splicing and 3 missense, which affected highly conserved amino acids). All mutations co-segregated with disease, and were not found in controls. Recent work by Loeys et al. examined ten families and described a new aortic aneurysm syndrome characterized by hypertelorism, bifid uvula/cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection, now called Loeys-Dietz Syndrome (LDS). Mutations in the TGFBR1 and TGFBR2 genes were associated with disease2. While there are some overlapping features between MS and LDS, ectopia lentis seems to be a very rare finding in individuals with TGFBR mutations, and LDS patients often have craniofacial abnormalities such as hypertelorism, and bifid uvula.
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FBN1, TGFBR1 and TGFBR2 Gene Mutation Analysis Assay Summary
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