Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 17, Issue 4, Pages 491-501Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2008.207
Keywords
Neonatal Marfan syndrome; FBN1 mutations; exons 24-32; clinical and mutation-type analysis
Funding
- French ministry of health
- GIS maladies rares 2004
- Bourse de la Socie te Francaise de Cardiologie
- Fe de ration Francaise de Cardiologie
- ANR [ANR-05-PCOD-014]
- Fund for Scientific Research -Flanders
- Marfan Trust
- Bluff Field Charitable Fund
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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.
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