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

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.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
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.

scholarly journals LTBP1 promotes fibrillin incorporation into the extracellular matrix

2021 ◽  
Author(s):  
Matthias Przyklenk ◽  
Veronika Georgieva ◽  
Fabian Metzen ◽  
Sebastian Mostert ◽  
Birgit Kobbe ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Wide Spectrum ◽  
Extracellular Matrix Protein ◽  
Connective Tissues ◽  
Pathogenic Variants ◽  
Human Pathology ◽  
Fibrillin 1

LTBP1 is a large extracellular matrix protein and an associated ligand of fibrillin-microfibrils. Knowledge of LTBP1 functions is largely limited to its role in targeting and sequestering TGFβ growth factors within the extracellular matrix, thereby regulating their bioavailability. However, the recent description of a wide spectrum of phenotypes in multiple tissues in patients harboring LTBP1 pathogenic variants suggests a multifaceted role of the protein in the homeostasis of connective tissues. To better understand the human pathology caused by LTBP1 deficiency it is important to investigate its functional role in extracellular matrix formation. In this study, we show that LTBP1 coordinates the incorporation of fibrillin-1 and -2 into the extracellular matrix in vitro. We also demonstrate that this function is differentially exerted by the two isoforms, the short and long forms of LTBP1. Thereby our findings uncover a novel TGFβ-independent LTBP1 function potentially contributing to the development of connective tissue disorders.

scholarly journals Cardiomyopathy in Genetic Aortic Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Muiño-Mosquera ◽  
Julie De Backer
Keyword(s):  
Marfan Syndrome ◽  
Myocardial Dysfunction ◽  
Genetic Defect ◽  
Positive Family History ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Aortic Diseases ◽  
Pathogenic Variants ◽  
Fibrillin 1

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

scholarly journals A Case of Neonatal Marfan Syndrome: A Management Conundrum and the Role of a Multidisciplinary Team

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Elliott J. Carande ◽  
Samuel J. Bilton ◽  
Satish Adwani
Keyword(s):  
Marfan Syndrome ◽  
Surgical Intervention ◽  
Rare Condition ◽  
Mitral Valve Regurgitation ◽  
Left Ventricular ◽  
Cardiac Complications ◽  
Chromosome 15 ◽  
Fibrillin 1 ◽  
Neonatal Marfan Syndrome

Neonatal Marfan syndrome (nMFS) is a rare condition with a poor prognosis. It is genotypically and phenotypically distinct from the typical Marfan syndrome and carries a poorer prognosis. This case report describes the progression of a 14-month-old girl diagnosed with nMFS at 5 months of age. Her diagnosis followed the identification of a fibrillin-1 mutation (FBN1gene, exon 26, chromosome 15), which is a common locus of nMFS. This patient developed severe cardiac complications resulting in congestive cardiac failure in early life and required major cardiac surgery. Since surgical intervention, our patient is still reliant on a degree of ventilator support, but the patient has gained weight and echocardiography has demonstrated improved left ventricular function and improved tricuspid and mitral valve regurgitation. Therefore, we argue the importance of a cautious multidisciplinary approach to early surgical intervention in cases of nMFS.

scholarly journals Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability

Genes ◽  
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.

A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome

2021 ◽  
pp. jmedgenet-2020-107604
Author(s):  
Paula Fernández-Álvarez ◽  
Marta Codina-Sola ◽  
Irene Valenzuela ◽  
Gisela Teixidó-Turá ◽  
Anna Cueto-González ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
De Novo ◽  
Normal Population ◽  
Genetic Disorders ◽  
Somatic Mosaicism ◽  
Clinical Signs ◽  
Systematic Analysis ◽  
Pathogenic Variants ◽  
Fibrillin 1 ◽  
Minor Criteria

BackgroundA proportion of de novo variants in patients affected by genetic disorders, particularly those with autosomal dominant (AD) inheritance, could be the consequence of somatic mosaicism in one of the progenitors. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. In Marfan syndrome (MFS), caused by pathogenic variants in the fibrillin-1 gene (FBN1) gene, approximately 25% of the disease-causing variants are reported as de novo. Only a few cases of parental mosaicism have been reported in MFS.MethodsEmploying an amplicon-based deep sequencing (ADS) method, we carried out a systematic analysis of 60 parents of 30 FBN1 positive, consecutive patients with MFS with an apparently de novo pathogenic variant.ResultsOut of the 60 parents studied (30 families), the majority (n=51, 85%) had a systemic score of 0, seven had a score of 1 and two a score of 2, all due to minor criteria common in the normal population. We detected two families with somatic mosaicism in one of the progenitors, with a rate of 6.6% (2/30) of apparently de novo cases.ConclusionsThe search for parental somatic mosaicism should be routinely implemented in de novo cases of MFS, to offer appropriate genetic and reproductive counselling as well as to reveal masked, isolated clinical signs of MFS in progenitors that may require specific follow-up.

scholarly journals Neurophysiological assessment in a patient affected by Marfan syndrome

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052097921
Author(s):  
Emanuele Cartella ◽  
Simona De Salvo ◽  
Katia Micchìa ◽  
Laura Romeo ◽  
Anna Lisa Logiudice ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Evoked Potential ◽  
Connective Tissue Disorder ◽  
Laser Evoked Potentials ◽  
Case Presentation ◽  
Future Studies ◽  
Nociceptive Pathways ◽  
Neurophysiological Studies ◽  
Neurophysiological Assessment

Background Marfan syndrome (MS) is a hereditary connective tissue disorder characterized by different multiorgan patterns. The guidelines for MS diagnosis do not highlight the usefulness—or even the use—of any neurophysiological techniques for diagnosing this disease. Moreover, few neurophysiological studies assessing the central and peripheral nervous systems in MS subjects have been reported to date. Case presentation: We describe a male patient affected by MS. To assess sensory and nociceptive pathways in this patient, a neurophysiological assessment was performed using electroencephalogram, nerve conduction studies, and somatosensory and laser-evoked potentials. To the best of our knowledge, this is the first published case report to evaluate the role of evoked potential assessments for the study of sensory and nociceptive pathways in MS. Conclusion Future studies should investigate the use of a complete neurophysiological approach for the clinical and therapeutic management of MS patients in a large sample.

scholarly journals Cooperative Mechanism of ADAMTS/ ADAMTSL and Fibrillin-1 in the Marfan Syndrome and Acromelic Dysplasias

2021 ◽  
Vol 12 ◽  
Author(s):  
Pauline Arnaud ◽  
Zakaria Mougin ◽  
Catherine Boileau ◽  
Carine Le Goff
Keyword(s):  
Marfan Syndrome ◽  
Wide Spectrum ◽  
Genetic Data ◽  
Mirror Image ◽  
Pathogenic Mechanism ◽  
Unique Combination ◽  
Multisystem Disease ◽  
Fibrillin 1 ◽  
Joint Limitation

The term “fibrillinopathies” gathers various diseases with a wide spectrum of clinical features and severity but all share mutations in the fibrillin genes. The first described fibrillinopathy, Marfan syndrome (MFS), is a multisystem disease with a unique combination of skeletal, thoracic aortic aneurysm (TAA) and ocular features. The numerous FBN1 mutations identified in MFS are located all along the gene, leading to the same pathogenic mechanism. The geleophysic/acromicric dysplasias (GD/AD), characterized by short stature, short extremities, and joint limitation are described as “the mirror image” of MFS. Previously, in GD/AD patients, we identified heterozygous FBN1 mutations all affecting TGFβ-binding protein-like domain 5 (TB5). ADAMTS10, ADAMTS17 and, ADAMTSL2 are also involved in the pathogenic mechanism of acromelic dysplasia. More recently, in TAA patients, we identified mutations in THSD4, encoding ADAMTSL6, a protein belonging to the ADAMTSL family suggesting that ADAMTSL proteins are also involved in the Marfanoid spectrum. Together with human genetic data and generated knockout mouse models targeting the involved genes, we provide herein an overview of the role of fibrillin-1 in opposite phenotypes. Finally, we will decipher the potential biological cooperation of ADAMTS-fibrillin-1 involved in these opposite phenotypes.

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