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Updated: Jun 28, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32
L Faivre1, G Collod-Beroud, B Callewaert
1Centre de Génétique, CHU, Dijon, France. laurence.faivre@chu-dijon.fr
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.
Insights
FBN1 gene mutations in exons 24-32 are linked to Marfan syndrome (MFS) severity. Mutation type, not just location, influences MFS presentation and cardiovascular risks.
Area of Science:
- Genetics
- Molecular Biology
- Cardiology
Background:
- Mutations in the FBN1 gene are the primary cause of Marfan syndrome (MFS).
- The region spanning exons 24-32 of FBN1 is associated with severe MFS phenotypes, particularly neonatal cases.
- Previous research indicated that mutations in this region predict severe cardiovascular issues and under-representation of premature truncation codons.
Purpose of the Study:
- To investigate the clinical and molecular characteristics of patients with FBN1 mutations in the 'neonatal' region (exons 24-32).
- To compare the phenotypes of patients with premature termination codons (PTCs) versus in-frame mutations within exons 24-32.
- To identify factors influencing MFS severity and presentation within this specific mutation region.
Main Methods:
- Analysis of clinical and molecular data from 198 probands with FBN1 mutations in exons 24-32.
- Comparison of phenotypic features between patients with PTCs and in-frame mutations in the specified region.
- Statistical analysis to determine the association between mutation type, location (exon 25), and clinical outcomes.
Main Results:
- In-frame mutations in exons 24-32 were associated with a higher probability of ectopia lentis and mitral insufficiency compared to PTCs.
- PTC mutations in exons 24-32 rarely resulted in neonatal or severe MFS.
- Mutations in exon 25 showed a higher likelihood of neonatal presentations and cardiovascular manifestations; recurrent mutations exhibited significant phenotypic heterogeneity.
Conclusions:
- While FBN1 exons 24-32 mutations are a major determinant of MFS severity, other factors like mutation type (PTC vs. in-frame) and potential modifier genes also play a significant role.
- The specific type of FBN1 mutation within the exons 24-32 region influences the clinical presentation and risk of specific MFS complications.
- Further research into genetic modifiers is warranted to fully understand the phenotypic variability observed in Marfan syndrome.
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