Abstract:Background
Marfan syndrome (MFS) is a systemic connective tissue disorder with life-threatening manifestations affecting the ascending aorta. MFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of the FBN1 gene. Our aim was to identify mutations of MFS patients with high detection rate and to investigate the use of a gene panel for patients with Marfanoid habitus. We also aimed to examine correlations between genotype and cardiovascular manifestations to predict “malign… Show more
“…In case of the latter group, current guidelines could be applied. This approach has been proposed in our previous work for patients with MFS [ 80 ], and the above reviewed results seem to strengthen this potential management strategy. Fig.…”
“…In addition, patients with DN Cys variants required aortic surgery more frequently than patients with HI and DN non-Cys mutations. Therefore, in our study DN Cys mutations appeared to be more deleterious than HI ones [ 80 ]. Similarly, when genotype–phenotype correlations were assessed in a pediatric cohort, missense variants affecting a cysteine showed a higher rate of sinuses of Valsalva dilation than missense mutations not affecting cysteine.…”
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.
“…In case of the latter group, current guidelines could be applied. This approach has been proposed in our previous work for patients with MFS [ 80 ], and the above reviewed results seem to strengthen this potential management strategy. Fig.…”
“…In addition, patients with DN Cys variants required aortic surgery more frequently than patients with HI and DN non-Cys mutations. Therefore, in our study DN Cys mutations appeared to be more deleterious than HI ones [ 80 ]. Similarly, when genotype–phenotype correlations were assessed in a pediatric cohort, missense variants affecting a cysteine showed a higher rate of sinuses of Valsalva dilation than missense mutations not affecting cysteine.…”
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.
“…The second one classified DN variants based on the affected region, including the N-terminus, C-terminus, and neonatal region. Recent studies suggested that DN (-Cys) variants and variants in the neonatal region were closer to HI variants in nature than other DN variants, ( Faivre et al, 2009b ; Stengl et al, 2020 ), while DN (+Cys) variants were associated with fewer aortic events but similarly high incidence of EL when compared to DN (-Cys) ( Faivre et al, 2007 ; Stengl et al, 2020 ; Arnaud et al, 2021a ). A new region was also identified by taking both the protein structure and the variant clusters of extreme phenotypes ( Takeda et al, 2018 ).…”
Marfan syndrome (MFS, OMIM: 154700) is a heritable multisystemic disease characterized by a wide range of clinical manifestations. The underlying molecular defect is caused by variants in the FBN1. Meanwhile, FBN1 variants are also detected in a spectrum of connective tissue disorders collectively termed as ‘type I fibrillinopathies’. A multitude of FBN1 variants is reported and most of them are unique in each pedigree. Although MFS is being considered a monogenic disorder, it is speculated that the allelic heterogeneity of FBN1 variants contributes to various manifestations, distinct prognoses, and differential responses to the therapies in affected patients. Significant progress in the genotype–phenotype correlations of MFS have emerged in the last 20 years, though, some of the associations were still in debate. This review aims to update the recent advances in the genotype-phenotype correlations of MFS and related fibrillinopathies. The molecular bases and pathological mechanisms are summarized for better support of the observed correlations. Other factors contributing to the phenotype heterogeneity and future research directions were also discussed. Dissecting the genotype-phenotype correlation of FBN1 variants and related disorders will provide valuable information in risk stratification, prognosis, and choice of therapy.
“…Fbn1 -mutant mouse models have been used in numerous studies for several years. The etiology of MFS has been ascribed to dominant-negative effects and haploinsufficiency [ 24 ]. The effect of FBN1 mutations in patients with MFS has been successfully mimicked in mouse models [ 19 ].…”
Section: Marfan Syndrome and Animal Modelsmentioning
Recent developments in reproductive biology have enabled the generation of genetically engineered pigs as models for inherited human diseases. Although a variety of such models for
monogenic diseases are currently available, reproduction of human diseases caused by haploinsufficiency remains a major challenge. The present study compares the phenotypes of mouse and pig
models of Marfan syndrome (MFS), with a special focus on the expressivity and penetrance of associated symptoms. Furthermore, investigation of the gene regulation mechanisms associated with
haploinsufficiency will be of immense utility in developing faithful MFS pig models.
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