Submission Details

The first report indicating a relationship between the FBN1 gene and autosomal dominant Marfan syndrome was reported by Dietz et al in 1991 (PMID: 1852208). The nomenclature for Marfan syndrome is ascribed to Antoine Marfan, who described a individual with part of the phenotypic features associated with the greater syndrome in 1896 (reviewed in Gott 1998, PMID: 9798380). Marfan syndrome a multisystemic disorder affecting mainly the connective tissue. Marfan comprises a broad phenotypic spectrum and severity and thus represents a continuum of disease (reviewed in Dietz 1991, Marfan GeneReviews, PMID: 20301510). Cardiovascular, ocular, and skeletal phenotypes represent the most common phenotypic manifestations among individuals diagnosed with Marfan syndrome. The cardiovascular phenotypes, including dilatation of the aorta, are the areas that represent the major morbidity and mortality of Marfan syndrome. Over 1800 variants have been identified in FBN1 (Collod-Beroud et al., 2003 PMID: 12938084), including missense, nonsense, frameshift, splice site, small deletions, and large deletions, according to two databases that house variant information: (1) The UMD-FBN1 database (http://www.umd.be/FBN1/); and (2) the LOVD FBN1 database (https://databases.lovd.nl/shared/genes/FBN1). The mechanism for the gene-disease relationship is protein loss of function, as mutation in the the FBN1 protein, fibrillin, results in the inability of the protein to be excreted from cells to help in the formation and stabilization of connective tissue (Sakai et al., 1986, PMID: 3536967). Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 20 years, therefore a significant amount of case-level data, segregation data, and experimental data is available and the maximum score for genetic evidence (12 points) and experimental evidence (6 points) has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. In particular, earlier compelling evidence suggestive of the gene-disease relationship, such as linkage data, may not be reflected in the current curation.

In summary, FBN1 is definitively associated with autosomal dominant Marfan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was reviewed by the FBN1 VCEP with final approval by the ClinGen General GCEP on March 4, 2019 (SOP Version 6).