Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome

Marfan syndrome (MFS) is a rare connective tissue disorder mainly due to mutations in the FBN1 gene. Great phenotypic variability is notable for age of onset, the presence and absence, and the number and the severity of the symptoms. Our team showed that FBN1 gene expression level was a good surrogate endpoint for severity of some MFS clinical features. Eight alternative transcripts are referenced for the FBN1 gene. We hypothesized that MFS clinical variability could be related to specific FBN1 isoforms. Isoform expression profiles were investigated in skin and adventitial fibroblasts from controls and MFS patients. The results of the study showed that, in skin and adventitial fibroblasts, only three isoforms were found: FBN1_001, FBN1_004, and FBN1_009. The main isoform was FBN1_001 and it was significantly reduced in skin and adventitial fibroblasts of MFS patients. The expressions of FBN1_004 and FBN1_009 isoforms were similar between controls and MFS patients. However, the expression of the three isoforms was correlated only in patients. Furthermore, their expression levels were associated with the presence of ectopia lentis in MFS patients. Therefore, our results highlight that the two minor alternatively spliced FBN1 isoforms play a possible role in the pathogenesis of the disease.

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Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability

Genes ◽

10.3390/genes11050574 ◽

2020 ◽

Vol 11 (5) ◽

pp. 574

Author(s):

Thomas Grange ◽

Mélodie Aubart ◽

Maud Langeois ◽

Louise Benarroch ◽

Pauline Arnaud ◽

...

Keyword(s):

Marfan Syndrome ◽

Clinical Features ◽

Familial Aggregation ◽

Phenotypic Variability ◽

Connective Tissue Disorder ◽

Clinical Feature ◽

Phenotypic Variance ◽

Genetic Modifiers ◽

Clinical Variability ◽

New Strategy

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the “Carter effect” in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity.

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Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression

Genes ◽

10.3390/genes9090421 ◽

2018 ◽

Vol 9 (9) ◽

pp. 421 ◽

Cited By ~ 2

Author(s):

Louise Benarroch ◽

Mélodie Aubart ◽

Marie-Sylvie Gross ◽

Marie-Paule Jacob ◽

Pauline Arnaud ◽

...

Keyword(s):

Gene Expression ◽

Marfan Syndrome ◽

Messenger Rna ◽

Calcium Influx ◽

Surrogate Endpoint ◽

Connective Tissue Disorder ◽

Eqtl Analysis ◽

Chromosome 11 ◽

Fbn1 Gene ◽

The Impact

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that displays a great clinical variability. Previous work in our laboratory showed that fibrillin-1 (FBN1) messenger RNA (mRNA) expression is a surrogate endpoint for MFS severity. Therefore, an expression quantitative trait loci (eQTL) analysis was performed to identify trans-acting regulators of FBN1 expression, and a significant signal reached genome-wide significant threshold on chromosome 11. This signal delineated a region comprising one expressed gene, SLN (encoding sarcolipin), and a single pseudogene, SNX7-ps1 (CTD-2651C21.3). We first investigated the region and then looked for association between the genes in the region and FBN1 expression. For the first time, we showed that the SLN gene is weakly expressed in skin fibroblasts. There is no direct correlation between SLN and FBN1 gene expression. We showed that calcium influx modulates FBN1 gene expression. Finally, SLN gene expression is highly correlated to that of the neighboring SNX7-ps1. We were able to confirm the impact of calcium influx on FBN1 gene expression but we could not conclude regarding the role of sarcolipin and/or the eQTL locus in this regulation.

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Phenotypic Variability in Marfan Syndrome in a Family With a Novel Nonsense FBN1 Gene Mutation

Revista Española de Cardiología (English Edition) ◽

10.1016/j.rec.2011.05.031 ◽

2012 ◽

Vol 65 (4) ◽

pp. 380-381 ◽

Cited By ~ 1

Author(s):

Aránzazu Díaz de Bustamante ◽

Eva Ruiz-Casares ◽

M. Teresa Darnaude ◽

Teresa Perucho ◽

Gabriel Martínez-Quesada

Keyword(s):

Gene Mutation ◽

Marfan Syndrome ◽

Phenotypic Variability ◽

Fbn1 Gene

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A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome

BioMed Research International ◽

10.1155/2018/3536495 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Mario Torrado ◽

Emilia Maneiro ◽

Juan Pablo Trujillo-Quintero ◽

Arturo Evangelista ◽

Alexander T. Mikhailov ◽

...

Keyword(s):

Connective Tissue ◽

Marfan Syndrome ◽

Premature Termination Codon ◽

Connective Tissue Disorder ◽

Aortic Dilatation ◽

Functional Protein ◽

Fbn1 Gene ◽

Intronic Mutation ◽

Aortic Pathology ◽

Fibrillin 1

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.

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Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Genes ◽

10.3390/genes10100764 ◽

2019 ◽

Vol 10 (10) ◽

pp. 764 ◽

Cited By ~ 4

Author(s):

Camerota ◽

Ritelli ◽

Wischmeijer ◽

Majore ◽

Cinquina ◽

...

Keyword(s):

Cervical Spine ◽

Connective Tissue ◽

Spontaneous Pneumothorax ◽

Age Of Onset ◽

Phenotypic Variability ◽

Connective Tissue Disorder ◽

Cervical Spine Instability ◽

Cutaneous Manifestations ◽

Life Threatening ◽

Arterial Aneurysms

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

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Clinical relevance of genotype–phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants

Genetics in Medicine ◽

10.1038/s41436-021-01132-x ◽

2021 ◽

Author(s):

Pauline Arnaud ◽

Olivier Milleron ◽

Nadine Hanna ◽

Jacques Ropers ◽

Nadia Ould Ouali ◽

...

Keyword(s):

Marfan Syndrome ◽

Phenotypic Variability ◽

Premature Termination Codon ◽

Connective Tissue Disorder ◽

Vascular Events ◽

Severe Scoliosis ◽

Pathogenic Variants ◽

Fibrillin 1 ◽

Cysteine Content

Abstract Purpose Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype–phenotype correlations have been found in proband studies only. Methods In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype–phenotype correlations. Results A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants. Conclusion This study shows that FBN1 genotype–phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.

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Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients

Genetics Research ◽

10.1017/s0016672316000112 ◽

2016 ◽

Vol 98 ◽

Cited By ~ 1

Author(s):

RUSTAM ZHURAYEV ◽

DORIEN PROOST ◽

DMYTRO ZERBINO ◽

VIKTOR FEDORENKO ◽

JOSEPHINA A. N. MEESTER ◽

...

Keyword(s):

Genetic Testing ◽

Marfan Syndrome ◽

Aortic Surgery ◽

Gene Mutations ◽

Cardiovascular Complications ◽

Connective Tissue Disorder ◽

Targeted Next Generation Sequencing ◽

Fbn1 Gene ◽

Significant Difference ◽

Life Threatening

SummaryMarfan syndrome is an autosomal dominant connective tissue disorder, predominantly affecting the ocular, skeletal and cardiovascular systems. Here, we present the results of the first genetic testing in 40 Ukrainian Marfan (-like) patients and 10 relatives. We applied a targeted next generation sequencing panel comprising FBN1 and 13 thoracic aortic aneurysm genes. We identified 27 causal mutations in FBN1, obtaining a mutation yield of 67·5%. A significant difference in age at aortic surgery between mutation positive and negative patients was observed. Thus, we conclude that genetic testing is important to identify patients at higher risk for developing life-threatening cardiovascular complications.

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Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

Genetics in Medicine ◽

10.1038/s41436-020-01078-6 ◽

2021 ◽

Author(s):

Pauline Arnaud ◽

Hélène Morel ◽

Olivier Milleron ◽

Laurent Gouya ◽

Christine Francannet ◽

...

Keyword(s):

Marfan Syndrome ◽

Somatic Mosaicism ◽

Variant Calling ◽

Copy Number Variations ◽

Pathogenic Variant ◽

Single Nucleotide Variants ◽

Bioinformatics Analyses ◽

Single Nucleotide ◽

Fbn1 Gene ◽

Pathogenic Variants

Abstract 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.

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Parental mosaicism in Marfan and Ehlers–Danlos syndromes and related disorders

European Journal of Human Genetics ◽

10.1038/s41431-020-00797-3 ◽

2021 ◽

Author(s):

Bertrand Chesneau ◽

Aurélie Plancke ◽

Guillaume Rolland ◽

Nicolas Chassaing ◽

Christine Coubes ◽

...

Keyword(s):

High Resolution ◽

Marfan Syndrome ◽

High Resolution Melting ◽

De Novo ◽

Direct Sequencing ◽

Causal Variant ◽

Connective Tissue Disorder ◽

High Resolution Melting Analysis ◽

Aortic Diseases ◽

Melting Analysis

AbstractMarfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our “aortic diseases genes” NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient’s management.

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Potential predictors of severe cardiovascular involvement in Marfan syndrome: the emphasized role of genotype–phenotype correlations in improving risk stratification—a literature review

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01882-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Roland Stengl ◽

Bence Ágg ◽

Miklós Pólos ◽

Gábor Mátyás ◽

Gábor Szabó ◽

...

Keyword(s):

Risk Stratification ◽

Marfan Syndrome ◽

Current Knowledge ◽

Imaging Techniques ◽

Connective Tissue Disorder ◽

Main Body ◽

Wide Range ◽

Stratification System ◽

Genetically Determined ◽

Aortic Dissections

Abstract Background Marfan syndrome (MFS) is a genetically determined systemic connective tissue disorder, caused by a mutation in the FBN1 gene. In MFS mainly the cardiovascular, musculoskeletal and ocular systems are affected. The most dangerous manifestation of MFS is aortic dissection, which needs to be prevented by a prophylactic aortic root replacement. Main body The indication criteria for the prophylactic procedure is currently based on aortic diameter, however aortic dissections below the threshold defined in the guidelines have been reported, highlighting the need for a more accurate risk stratification system to predict the occurrence of aortic complications. The aim of this review is to present the current knowledge on the possible predictors of severe cardiovascular manifestations in MFS patients, demonstrating the wide range of molecular and radiological differences between people with MFS and healthy individuals, and more importantly between MFS patients with and without advanced aortic manifestations. These differences originating from the underlying common molecular pathological processes can be assessed by laboratory (e.g. genetic testing) and imaging techniques to serve as biomarkers of severe aortic involvement. In this review we paid special attention to the rapidly expanding field of genotype–phenotype correlations for aortic features as by collecting and presenting the ever growing number of correlations, future perspectives for risk stratification can be outlined. Conclusions Data on promising biomarkers of severe aortic complications of MFS have been accumulating steadily. However, more unifying studies are required to further evaluate the applicability of the discussed predictors with the aim of improving the risk stratification and therefore the life expectancy and quality of life of MFS patients.

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