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Published on: August 15, 2019
Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome
R A Montgomery1, M T Geraghty, E Bull
1Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Abstract:
Mutations in the FBN1 gene, which encodes fibrillin-1, cause Marfan syndrome (MFS) and have been associated with a wide range of milder, overlap phenotypes. The factors that modulate phenotypic severity, both between and within families, remain to be determined. This study examines the relationship between the FBN1 genotype and phenotype in families with extremely mild phenotypes and in those that show striking clinical variation among apparently affected individuals. In one family, clinically similar but etiologically distinct disorders are segregating independently. In another, somatic mosaicism for a mutant FBN1 allele is associated with subdiagnostic manifestations, whereas germ-line transmission of the identical mutation causes severe and rapidly progressive disease. A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype. These data have immediate relevance for the diagnostic and prognostic counseling of patients and their family members.
Insights
Genetic variations in the FBN1 gene explain diverse Marfan syndrome (MFS) phenotypes. This study reveals how FBN1 mutations, including somatic mosaicism, influence disease severity and presentation, aiding in patient diagnosis and prognosis.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Medicine
Background:
- Marfan syndrome (MFS) is caused by mutations in the FBN1 gene, encoding fibrillin-1.
- Phenotypic variability in MFS, even within families, is significant and not fully understood.
- Factors modulating MFS severity require further investigation.
Purpose of the Study:
- To investigate the relationship between FBN1 genotype and phenotype in individuals with mild or variable MFS.
- To explore the impact of distinct FBN1 mutations and inheritance patterns on disease expression.
- To provide insights into the genetic basis of phenotypic diversity in FBN1-related disorders.
Main Methods:
- Analysis of FBN1 gene mutations in families exhibiting mild or variable MFS phenotypes.
- Clinical assessment of affected individuals to correlate genotype with specific manifestations.
- Functional characterization of FBN1 mutations to understand their impact on fibrillin-1 function.
Main Results:
- Identified distinct genetic etiologies for clinically similar disorders within a single family.
- Demonstrated that somatic mosaicism for an FBN1 mutation can lead to subdiagnostic symptoms, while germline transmission causes severe disease.
- Correlated a specific FBN1 mutation with mild mitral valve prolapse syndrome, distinct from classic MFS mutations.
Conclusions:
- FBN1 genotype plays a crucial role in determining the spectrum and severity of Marfan syndrome and related disorders.
- Somatic mosaicism and specific mutation characteristics significantly influence phenotypic presentation.
- Findings are vital for accurate diagnosis, prognosis, and genetic counseling for MFS patients and families.
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