Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24–32 mutation (original) (raw)
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Mutations identified in the fibrillin-1 (FBN1) gene have been associated with Marfan syndrome (MFS). Molecular analysis of the gene is classically performed in probands with MFS to offer diagnosis for at-risk relatives and in children highly suspected of MFS. However, FBN1 gene mutations are found in an ill-defined group of diseases termed 'type I fibrillinopathies', which are associated with an increased risk of aortic dilatation and dissection. Thus, there is growing awareness of the need to identify these non-MFS probands, for which FBN1 gene screening should be performed. To answer this need we compiled the molecular data obtained from the screening of the FBN1 gene in 586 probands, which had been addressed to our laboratory for molecular diagnosis. In this group, the efficacy of FBN1 gene screening was high in classical MFS probands (72.5%,), low (58%) in those referred for incomplete MFS and only slight (14.3%) for patients referred as possible MFS. Using recursive partitioning, we found that the best predictor of the identification of a mutation in the FBN1 gene was the presence of features in at least three organ systems, combining one major, and various minor criteria. We also show that our original recommendation of two systems involved with at least one with major criterion represents the minimal criteria because in probands not meeting these criteria, the yield of mutation identification drastically falls. This recommendation should help clinicians and biologists in identifying probands with a high probability of carrying a FBN1 gene mutation, and thus optimize biological resources.
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Each line represents a single FBN1 mutation. The columns contain the following information and abbreviations: Column A: File number. Column B: Exon number at which the mutation is located. Column C: Nucleotide position at which the mutation is located. Column D: Codon number at which the mutation is located. Column E: Normal base sequence of the codon in which the mutation occurred. Column F: Mutated base sequence of the codon in which the mutation occurred. Column G: Concerns base substitutions. It gives the base change, by convention, read from the coding strand. If the mutation predicts a premature protein-termination, the novel stop codon position is given, e.g. 'Stop at 2115'. Column H: Mutation name according to Beaudet et al. (44). Column I: Wild type amino acid. Column J: Mutant amino acid. Deletion and insertion mutations which result in a frameshift are designated by 'Frameshift'. Nonsense mutations are designated by 'Stop'. Column K: Protein domain in which the mutation occurs. Each motif group is numbered separately and according to their position with respect to the N-terminal end of the protein, e.g. 'cb EGF-like' (for calcium-binding EGF-like motifs) #1-43, 'EGF-like' (for non calcium-binding EGF-like motifs) #1-4, '8-cys' (for '8-cysteine' motifs) #1-7, 'Hybrid motifs' #1 and 2 (3-5). Column L-Q: Diagnostic manifestations in the systems listed by Beighton et al. (45) and De Paepe et al. (46). In all these columns, '?' indicates either lack of or unspecified data until more precise information is available. Column L: Presence (+) or absence (-) of skeletal manifestations. Column M: Presence (+) or absence (-) of ocular manifestations. Column N: Presence (+) or absence (-) of cardiovascular manifestations. Column O: Presence (+) or absence (-) of pulmonary manifestations. Column P: Presence (+) or absence (-) of manifestations in skin and integument. Column Q: Presence (+) or absence (-) of manifestations in central nervous system. Column R: Reference number indicating the publication in which the mutation is described. NP indicates unpublished mutations contributed by NP1 (M. Boxer and C. Black) and NP2 (D. Milewicz). P indicates references that are in press.