Update of the UMD-FBN1mutation database and creation of anFBN1polymorphism database

Abstract

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS). FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS, called "type-1 fibrillinopathies." In 1995, in an effort to standardize the information regarding these mutations and to facilitate their mutational analysis and identification of structure/function and phenotype/genotype relationships, we created a human FBN1 mutation database, UMD-FBN1. This database gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. For each mutation, information is provided at the gene, protein, and clinical levels. This tool is now a worldwide reference and is frequently used by teams working in the field; more than 220,000 interrogations have been made to it since January 1998. The database has recently been modified to follow the guidelines on mutation databases of the HUGO Mutation Database Initiative (MDI) and the Human Genome Variation Society (HGVS), including their approved mutation nomenclature. The current update shows 559 entries, of which 421 are novel. UMD-FBN1 is accessible at www.umd.be/. We have also recently developed a FBN1 polymorphism database in order to facilitate diagnostics.

Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene

“…Among the 354 mutations detailed in this report, two mutations detected in this cohort have been described elsewhere (c.2954G4A and c.3965-2A4G (c.IVS31-2A4G)); 19,20 and 87 mutations have been made available to the community through the UMD-FBN1 website since 2003. 21,22 Mutations are distributed as follows: 196 missense mutations, 48 alterations affecting conserved splice sites, 55 nonsense mutations, 14 insertions/duplications, and 41 deletions. Among the mutations found, 188 (53.1%) were familial.…”

Three novel mutations of the fibrillin-1 gene and ten single nucleotide polymorphisms of the fibrillin-3 gene in Marfan syndrome patients

“…FBN1 on chromosome 15q21.1 codes for fibrillin-1, a main component of extracellular microfibrils. Since the identification of FBN1, over 550 mutations have been identified (Collod-Beroud et al 2003). Although the mutation detection rate varies from 23.5 to 80%, the overall mutation detection rate is approximately 50% even in patients with classic MFS.…”

The challenge of comprehensive and consistent sequence variant interpretation between clinical laboratories

“…If the variant had not been previously identified in the CDL, the variant was investigated per a protocol that included searching publicly available loci-specific and population databases, referencing conservation and assessing predicted protein effects (Supplementary Chart S1 online). The referenced databases included the Osteogenesis Imperfecta/ Ehlers-Danlos Syndrome International Database, 12,13 the Universal Mutation Database FBN1 mutations database, 14 the Universal Mutation Database TGFBR1 and TGFBR2 databases, 15 and the National Center for Biotechnology Information ClinVar database. 11 At the conclusion of the investigation, variants were classified as one of the following categories based on clinical assessment of the available evidence: pathogenic, likely pathogenic, VUS, likely benign, or benign.…”