Fig 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Summary of the genetic testing steps. Genetic screening steps for two sets of patients. We started the genetic testing with sequencing the FBN1 gene. The negative samples were further investigated with MLPA technique. We applied an NGS gene panel for the samples with repeated negative results. We applied the gene panel followed by MLPA for the second set of patients. The two phases of the study are indicated
Source publication
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...
Contexts in source publication
Context 1
... describe the general characteristics of the examined population, we calculated the mean and 95% confidence interval; for the systemic score, we used median with first and third interquartile range. Figure 1 shows the distribution of genetic screening steps applied for the two sets of patients and the results of the two phases of the study. ...
Similar publications
Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority
Background
Mitral valve prolapse is a common finding in patients with Marfan (MFS) and Loeys-Dietz syndromes (LDS). Mitral annulus disjunction (MAD) is an atrial displacement of the hinge point of the mitr...
Citations
... Number (N); not applicable (NA); variants that substitute a cysteine for another amino acid (Cys-); missense variants that substitute for a cysteine (Cys+); variants that do not modify cysteine content (Cys-no) It is interesting to note the differences in cardiovascular phenotype among the different variants of FBN1 gene in EOMFS patients, as well the potential impact on clinical management and prognosis. Variants resulting in cysteine alterations and haploinsufficiency, which were associated with higher aortic events risk, highlight the importance of regular cardiovascular monitoring and early intervention planning in these patients [12,54,55]. In addition, cys-variants also have the greater prevalence of mitral valve prolapse (MVP) and mitral annular disjunction (MAD). ...
... Patients with cys + genotypes should be more intensively screened for ectopia lentis, while haploinsufficiency patients should be closely monitored for cardiovascular state. Speaking of cys-and cys-no patient groups, a possible overlap within phenotype severity and eligibility for surgical intervention based on their genotype should be cautiously investigated in future genotype-phenotype studies, as other authors previously found similar results and suggested to optimise timing and decision making on the need for prophylactic aortic root surgery [54]. All EOMFS patients are at risk for some type of skeletal deformation and should be regularly examined by a pediatric orthopaedic traumatologist. ...
Background
Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants clustered in exons 24–32 of fibrillin-1 ( FBN1 ) gene result in more severe clinical phenotypes. Furthermore, genotype-phenotype correlation studies suggested that more severe cardiovascular phenotypes were related to variants held responsible for haploinsufficiency. Our objective was to analyze the differences in clinical manifestations and genotypes of individuals with early-onset Marfan syndrome and to assess their impact on management strategies.
Methods
We analyzed clinical and genetic data of a new patient with early-onset Marfan syndrome together with 51 previously reported ones in the PubMed database between 1991 and 2022.
Results
Analysis showed 94% (49/52) of pathogenic variants clustered in exons 24–32 of the FBN1 . The most common skeletal features were arachnodactyly (98%), reduced elbow extension (48%), pectus deformity (40%), and scoliosis (39%). Haploinsufficiency variants were reported as having poor outcome in 87.5% of the cases. Among patients carrying variants that substitute a cysteine for another amino acid and those that do not change cysteine content, cardiac intervention was found to be associated with a better outcome (p = 0.035 vs. p = 0.002). Variants that create an extra cysteine residue were found to be associated with a higher risk of ectopia lentis. Additionally, children up to 36-months-old were more often reported as still alive at the time of publication compared to newborns (p < 0.01).
Conclusions
Our findings have implications for prognosis, because different genotype groups and their resulting phenotype may require personalized care and management.
... Hence, cysmissense mutations or mutations occurred in cb-EGF domains could have resulted in a disulfide-bond loss, which render the protein more vulnerable to proteolysis. This pathophysiology has been implicated in particularly severe cardiovascular abnormalities [29][30][31]. ...
Purpose
Congenital ectopia lentis (CEL) and heart abnormalities are common clinical symptoms in patients with Marfan syndrome (MFS) and related fibrillinopathies, which is caused by mutations in fibrillin-1 (FBN1) gene. This study aims to explore the ocular and cardiovascular characteristics and their association with genotype in children with MFS and related fibrillinopathies.
Methods
Seventy-nine children diagnosed with CEL and with FBN1 mutations confirmed via whole-exome sequencing were included for genotypes and phenotypes analysis. The axial length (AL), corneal curvature, and refractive status were included for ocular phenotypes analysis. The cardiovascular examination was performed by echocardiography, and aortic root Z score was calculated to evaluate the severity of aortic dilatation. The heart disorders were classified as aortic root dilatation, valvular disorders, and others. Both the ocular and cardiac manifestations were collected for comprehensive analysis and compared among patients with different genotypes, including the mutation involving cysteine substitution or mutation in different regions.
Results
In CEL children with FBN1 mutations, 77.2% patients could be diagnosed as MFS. It was observed that children with mutations in exons 22–42 had significant higher aortic root Z score (P = 0.003) and higher incidence of cardiovascular disorders (P = 0.004). Additionally, children with cysteine substitution mutations had significant higher aortic root Z score (P = 0.011), and the aortic root Z score was positively associated with axial length (AL) in children under 6 years old (P = 0.035). Those with long AL (≥ 26 mm) had significant higher incidence of valve disorders (P = 0.023). In addition, nearly half the children with CEL (46.8%) were diagnosed with cardiovascular disease for the first time.
Conclusions
CEL children with FBN1 mutations involving cysteine substitution or mutations in exons 22–42 or with long AL had higher risks of severe cardiovascular complications. Knowing the phenotype may help in anticipating severe cardiovascular disease in CEL patients.
... The relative frequency of the reported FBN1 variants is about 66% for missense variants, 10-15% for small insertions, deletions, or duplications, and 10-15% for splicing errors most commonly affecting canonical splice sequences at exon/intron boundaries [39]. Larger rearrangements, including both deletions and insertions, although a minority, have been found in 3-7% of patients [40][41][42], while entire gene deletions are much rarer [43]. ...
Marfan syndrome (MFS) is a rare inherited autosomic disorder, which encompasses a variety of systemic manifestations caused by mutations in the Fibrillin-1 encoding gene (FBN1). Cardinal clinical phenotypes of MFS are highly variable in terms of severity, and commonly involve cardiovascular, ocular, and musculoskeletal systems with a wide range of manifestations, such as ascending aorta aneurysms and dissection, mitral valve prolapse, ectopia lentis and long bone overgrowth, respectively. Of note, an accurate and prompt diagnosis is pivotal in order to provide the best treatment to the patients as early as possible. To date, the diagnosis of the syndrome has relied upon a systemic score calculation as well as DNA mutation identification. The aim of this review is to summarize the latest MFS evidence regarding the definition, differences and similarities with other connective
tissue pathologies with severe systemic phenotypes (e.g., Autosomal dominant Weill–Marchesani syndrome, Loeys–Dietz syndrome, Ehlers–Danlos syndrome) and clinical assessment. In this regard, the management of MFS requires a multidisciplinary team in order to accurately control the evolution of the most severe and potentially life-threatening complications. Based on recent findings in the literature and our clinical experience, we propose a multidisciplinary approach involving specialists in different clinical fields (i.e., cardiologists, surgeons, ophthalmologists, orthopedics, pneumologists, neurologists, endocrinologists, geneticists, and psychologists) to comprehensively characterize, treat,
and manage MFS patients with a personalized medicine approach.
... Both subjects exhibited sufficient physical manifestations for a positive diagnosis (systemic score ≥ 7), and the presence of aortic involvement was well established. Genetic testing performed by means of next-generation and Sanger sequencing [33] identified different pathogenic mutations in the FBN1 gene ( Figure 1). MFS patient #1 carried a nonsense mutation leading to the premature termination of protein synthesis at the fourth cysteine residue of the fourth cbEGF domain. ...
Fibrillin-1 microfibrils are essential elements of the extracellular matrix serving as a scaffold for the deposition of elastin and endowing connective tissues with tensile strength and elasticity. Mutations in the fibrillin-1 gene (FBN1) are linked to Marfan syndrome (MFS), a systemic connective tissue disorder that, besides other heterogeneous symptoms, usually manifests in life-threatening aortic complications. The aortic involvement may be explained by a dysregulation of microfibrillar function and, conceivably, alterations in the microfibrils’ supramolecular structure. Here, we present a nanoscale structural characterization of fibrillin-1 microfibrils isolated from two human aortic samples with different FBN1 gene mutations by using atomic force microscopy, and their comparison with microfibrillar assemblies purified from four non-MFS human aortic samples. Fibrillin-1 microfibrils displayed a characteristic “beads-on-a-string” appearance. The microfibrillar assemblies were investigated for bead geometry (height, length, and width), interbead region height, and periodicity. MFS fibrillin-1 microfibrils had a slightly higher mean bead height, but the bead length and width, as well as the interbead height, were significantly smaller in the MFS group. The mean periodicity varied around 50–52 nm among samples. The data suggest an overall thinner and presumably more frail structure for the MFS fibrillin-1 microfibrils, which may play a role in the development of MFS-related aortic symptomatology.
... Several large cohorts with autosomal dominant inherited MFS and related diseases have been studied previously, and a definitive molecular diagnosis was reported in 40-95% of them depending on the testing strategy and inclusion criteria [11,27,28]. Currently, genetic approaches are preferred for testing individuals with MFS and Marfanoid habitus using a gene panel rather than single-gene analysis, followed by multiplex ligation-dependent probe amplification for negative samples because of the relevant number of mutations affecting genes other than FBN1 [29]. Particularly, targeted panel sequencing that includes a broader list of candidate genes as well as a better and more thorough evaluation of the clinical manifestations of MFS and Marfanoid habitus may improve genetic diagnoses considerably [13,14,23]. ...
Marfan syndrome (MFS) is a hereditary connective tissue disease whose clinical severity varies widely. Mutations of the FBN1 gene encoding fibrillin-1 are the most common genetic cause of Marfanoid habitus; however, about 10% of MFS patients are unaware of their genetic defects. Herein, we report a Korean patient with MFS and annuloaortic ectasia caused by an intronic c.5225-3C>G variant of the FBN1 gene identified by targeted panel sequencing. The reverse transcription analysis of FBN1 revealed that the intron 43 sequence from positions c.5297-1516 to c.5297-1 was retained at the coding sequence as a consequence of the c.5225-3C>G variant enhancing a cryptic splice acceptor site (c.5297-1518_5297-1517AG) in intron 43. The retained sequence of the part of intron 43 caused the same effect as insertion mutation (NM_000138.5:c.5297_c.5298ins5297-1516_5297-1), resulting in a frameshift mutation resulting in p.Ile1767Trpfs*3. The patient underwent an urgent modified Bentall operation with a 29 mm mechanical valve for annuloaortic ectasia and severe aortic valve regurgitation. This report emphasizes the need for functional investigations into the diagnostic workflows of certain diseases or gene panels with suspected high rates of intronic variants and potential pathogenic effects. Hence, further descriptions of individuals with intronic variants causing alternative splicing expected to have pathogenic effects at different transcript levels are crucial for improving our understanding.
... 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. ...
... Year of publication 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. However, before clinical application, further investigations are in need with larger patient cohorts and in a prospective manner in order to precisely estimate the risk of the certain mutation types. ...
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.
... Because of the clinical diagnosis of MFS, the patient took part in our ongoing genetic testing program for MFS and related disorders. A next-generation sequencing (NGS)-based multigene panel was applied to screen the following nine genes: ACTA2, COL3A1, FBN1, KCNN1, MYH11, SMAD3, TGFB2, TGFBR1, and TGFBR2 (13). A pathogenic mutation in the FBN1 gene was detected, confirming the diagnosis of MFS. ...
Marfan syndrome (MFS) is a genetically determined connective tissue disorder that leads to ocular, skeletal, and severe cardiovascular involvement. High mortality of MFS is associated with aortic dissection and aneurysm characteristic to the syndrome. In MFS, only a few cases of peripheral arterial involvement have been reported so far, mostly without a genetically confirmed diagnosis. We report a 41-year-old MFS patient with a saccular pearl-string-like aneurysm on the right internal mammary artery (RIMA) and a single aneurysm on the left internal mammary artery (LIMA). To our knowledge this is the first reported case on internal mammary artery aneurysms with this special morphology and with follow-up and blood pressure control as primary therapeutic approach in a patient with genetically confirmed MFS. The aneurysms with the above described morphology first appeared as small aneurysms on a CT scan 6 years after a cardiac operation. Due to the lack of guidelines, based on the asymptomatic state of the patient, the increased tortuosity of the affected vessels and the history of prior cardiac surgery, we decided to closely monitor these aneurysms with blood pressure control and without carrying out any interventions. On the CT scans done 3, 11, 12, 17, and 32 months after identifying the aneurysms, no progression of these structures was detected. Our findings confirm the possibility of the occurrence of internal mammary artery aneurysms in patients with FBN1 mutation and we believe that monitoring these aneurysms with blood pressure management can be a suitable option in selected cases.
... MFS is diagnosed according to criteria that incorporate clinical, family history, and genetic features (4), and ~20% of patients will not have a detectable mutation in the causally associated fibrillin 1 (FBN1) gene (5), although the medical and surgical recommendations discussed later are similar. Notably, in the absence of molecular confirmation through genetic testing, LDS may be misdiagnosed as MFS due to overlapping features (6). ...
In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed “Mendelian vascular diseases,” which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.
Purpose of review
This review aims to delineate the genetic basis of Marfan syndrome (MFS) and underscore the pivotal role of genetic testing in the diagnosis, differential diagnosis, genotype–phenotype correlations, and overall disease management.
Recent findings
The identification of pathogenic or likely pathogenic variants in the FBN1 gene, associated with specific clinical features such as aortic root dilatation or ectopia lentis, is a major diagnostic criterion for MFS. Understanding genotype–phenotype correlations is useful for determining the timing of follow-up, guiding prophylactic aortic root surgery, and providing more precise information to patients and their family members during genetic counseling. Genetic testing is also relevant in distinguishing MFS from other conditions that present with heritable thoracic aortic diseases, allowing for tailored and individualized management.
Summary
Genetic testing is essential in different steps of the MFS patients’ clinical pathway, starting from the phase of diagnosis to management and specific treatment.
