Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation.

Abstract

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.

• Authors: L Faivre, G Collod-Beroud, B Callewaert, A Child, C Binquet, E Gautier, B L Loeys, E Arbustini, K Mayer, M Arslan-Kirchner, C Stheneur, A Kiotsekoglou, P Comeglio, N Marziliano, J E Wolf, O Bouchot, P Khau-Van-Kien, C Beroud, M Claustres, C Bonithon-Kopp, P N Robinson, L Adès, J De Backer, P Coucke, U Francke, A De Paepe, G Jondeau, C Boileau
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 17 Issue 4 Pg. 491-501 (Apr 2009) ISSN: 1476-5438 [Electronic] England
• PMID: 19002209 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon, Nonsense
• FBN1 protein, human
• Fibrillin-1
• Fibrillins
• Microfilament Proteins

Topics

• Codon, Nonsense
• DNA Mutational Analysis
• Ectopia Lentis (genetics)
• Exons (genetics)
• Fibrillin-1
• Fibrillins
• Humans
• Marfan Syndrome (genetics)
• Microfilament Proteins (genetics, metabolism)
• Mutation
• Phenotype