Abstract
Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects) who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6% (24/34) of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported.
Highlights
Marfan syndrome (MFS; MIM 154700) is a relatively common autosomal dominant hereditary disorder of connective tissue (1:5,000-10,000 individuals) with prominent manifestations in the skeletal, ocular, and cardiovascular systems
The discovery that mutations in gene FBN1 cause MFS has increased the chances of identifying the disease in atypical or oligosymptomatic individuals through molecular diagnosis [25]
The more recent descriptions of mutations in other genes causing phenotypes overlapping with MFS have suggested the existence of genetic heterogeneity, or of a novel clinical entity, the Loeys-Dietz syndrome (LDS) [18,22,25,26,27]
Summary
Marfan syndrome (MFS; MIM 154700) is a relatively common autosomal dominant hereditary disorder of connective tissue (1:5,000-10,000 individuals) with prominent manifestations in the skeletal, ocular, and cardiovascular systems. Ectopia lentis affects up to 80% of individuals with MFS and is almost always bilateral [1,2,3]. The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which follows a period of progressive dilatation of the ascending aorta [4,5,6]. The disease is caused by mutations in the FBN1 gene at 15q21.1, encoding the large cysteine-rich extracellular matrix glycoprotein fibrillin-1, the major component of microfibrils. FBN1 spans a 230-kb genomic region with 65 exons and about 600 different reported mutations spread throughout the gene, mostly specific to each affected family [7,8,9,10,11,12,13]
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