Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome
Pauline Arnaud1,2,3, Hélène Morel1,4, Olivier Milleron1,3
1Université de Paris, Laboratory for Vascular Translational Science, INSERM U1148, Hôpital Bichat-Claude-Bernard, Paris, France.
Purpose:
Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands.
Methods:
Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene.
Results:
These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations.
Conclusion:
This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.
Insights
Mosaic pathogenic variants in the FBN1 gene are rare in Marfan syndrome (MFS) patients. This study identified five symptomatic MFS probands with mosaic FBN1 variants, highlighting the need for adapted diagnostic approaches.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Diseases
Background:
- Mosaic pathogenic variants in the FBN1 gene are infrequently reported.
- Literature primarily describes asymptomatic individuals identified through familial screening.
- Marfan syndrome (MFS) is a genetic disorder affecting connective tissue.
Purpose of the Study:
- To investigate the occurrence and clinical significance of mosaic pathogenic variants in the FBN1 gene among Marfan syndrome probands.
- To report the experience of a clinical team with over 5,000 MFS probands.
Main Methods:
- Utilized next-generation sequencing (NGS) capture technology.
- Analyzed data from over 5,000 Marfan syndrome probands.
- Identified five cases with mosaic pathogenic variants in the FBN1 gene.
Main Results:
- Five sporadic MFS probands with mosaic pathogenic variants in the FBN1 gene were identified.
- These individuals presented with classical Marfan syndrome features.
- Findings included both single-nucleotide variants and copy-number variations.
Conclusions:
- Mosaic FBN1 variants are an underestimated finding in MFS molecular diagnostics.
- Bioinformatics analysis parameters may require adaptation for mosaic variant detection.
- Symptomatic MFS probands with mosaic FBN1 variants necessitate thorough clinical evaluation and cardiovascular monitoring, including for potentially asymptomatic mosaic parents.
More Related Videos
09:37Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
03:45Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Related Concept Videos
01:33Pleiotropy
01:23Cystic Fibrosis: Pathogenesis
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
01:11Fibril-associated Collagen
For example, the type II collagen fibrils in cartilage have covalently bound type IX fibril-associated collagens at regular intervals. Other types of fibril-associated collagens are...
01:43Sex-linked Disorders
01:39Mutations
02:21Cancers Originate from Somatic Mutations in a Single Cell