Chapter 8: The Marfan Mutation Database

Mutations in the fibrillin gene (FBN1) were described at first in Marfan syndrome (MFS) patients. Subsequently, the gene was shown to harbor mutations related to a spectrum of conditions clinically related to MFS, the "type-1 fibrillinopathies". In an effort to standardize the information regarding these mutations, to facilitate their mutational analysis and the identification of structure/function and phenotype/genotype relationships, we created, in 1995, a mutation database named “UMD-FBN1”. The database follows the guidelines on mutation databases of the Hugo Mutation Database Initiative and gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. Recently, we have also developed a FBN1 polymorphism database in order to facilitate diagnosis. Mutations in the FBN1 gene are associated with a wide range of phenotypes that show considerable variation in tissue distribution, timing of onset, and severity. The severe end of this broad spectrum of phenotypes is neonatal MFS. Conditions at the mild end include the MASS syndrome (Mitral valve prolapse, Aortic dilatation, and Skin and Skeletal manifestations) (OMIM#604308), mitral valve prolapse syndrome (OMIM#157700), isolated skeletal features, familial ascending aortic aneurysm and dissection (OMIM#132900), and ectopia lentis (OMIM#129600) with relatively mild skeletal features. Many of these conditions show significant overlap with MFS and are quite common in the general population. Finally, two syndromes [dominant Weill-Marchesani1 and Shprintzen-Goldberg OMIM#182212] have also been associated with mutations in the FBN1 gene. In an effort to standardize the information regarding FBN1 mutations, we created a computerized database in 1995 using the UMD (Universal Mutation Database) software. This generic software was devised by Cariello et al. (ref 2) to create locus-specific databases (LSDBs) with the 4th Dimension® package from ACI2,3. The software includes an optimized structure to assist and secure data entry and to allow the input of clinical information. The software package contains routines for the analysis of the database. The use of the 4th Dimension ® (4D) SGDB gives access to optimized multicriteria research and sorting tools to select records from any field. The software has been successfully adapted to many different genes either involved in cancer (p532,4, APC5,6, VHL7,8, and WT19) or in genetic diseases (LDLR10-12, VLCAD (very long-chain acyl-CoA dehydrogenase) (unpublished) and MCAD (medium-chain acyl-CoA dehydrogenase) (unpublished)). Routines were specifically developed for the FBN1 database and are described below3,13-15