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Human Genome Variation Feb 2024Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and...
Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and crumpled ears. We report a case of a boy with suspected Marfan syndrome. Genetic analysis revealed c.3207_3217+9del in a heterozygote form of the fibrillin-2 (FBN2) gene. This patient was diagnosed with CCA based on his phenotype, and the pathogenicity of this variant was classified according to cDNA analysis and protein modeling.
PubMed: 38326314
DOI: 10.1038/s41439-024-00264-1 -
Heliyon Feb 2024Marfan syndrome (MS) is an autosomal dominant connective tissue disease associated with significant morbidity and mortality due to progressive dilatation of the thoracic...
Marfan syndrome (MS) is an autosomal dominant connective tissue disease associated with significant morbidity and mortality due to progressive dilatation of the thoracic aorta which can lead to aortic rupture. Survival from an aortic rupture is predicated on immediate organized and goal directed care by both surgical and anesthesia teams. This case highlights how coordinated care from a cardiac operating room team, including early preparation of autologous blood products, expeditious placement of intravascular access for rapid high volume transfusion, and intentional communication between anesthesia, perfusion, surgery and nursing during the resuscitation in the OR, can all lead to an improved outcome.
PubMed: 38322912
DOI: 10.1016/j.heliyon.2024.e25235 -
BMC Medical Genomics Feb 2024Mutations in fibrillin-1 (FBN1) are known to be associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder. Most FBN1 mutations are missense...
BACKGROUND
Mutations in fibrillin-1 (FBN1) are known to be associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder. Most FBN1 mutations are missense or nonsense mutations. Traditional molecular genetic testing for the FBN1 gene, like Sanger sequencing, may miss disease-causing mutations in the gene's regulatory regions or non-coding sequences, as well as partial or complete gene deletions and duplications.
METHODS
Next-generation sequencing, multiplex ligation-dependent probe amplification and gap PCR were conducted on two MFS patients to screen for disease-causing mutations.
RESULTS
We identified two large deletions in FBN1 from two MFS patients. One patient had a 0.23 Mb deletion (NC_000015.9:g.48550506_48779360del) including 5'UTR-exon6 of FBN1. The other patient harbored a 1416 bp deletion (NC_000015.9:g.48410869_48412284del) affecting the last exon, exon 66, of the FBN1 gene.
CONCLUSION
Our results expanded the number of large FBN1 deletions and highlighted the importance of screening for large deletions in FBN1 in clinical genetic testing, especially for those with the classic MFS phenotype.
Topics: Humans; Multiplex Polymerase Chain Reaction; Genetic Testing; Mutation; Marfan Syndrome; High-Throughput Nucleotide Sequencing; Fibrillin-1; Adipokines
PubMed: 38317175
DOI: 10.1186/s12920-024-01822-w -
Journal of Cardiovascular Magnetic...Four-dimensional (4D) flow magnetic resonance imaging (MRI) often relies on the injection of gadolinium- or iron-oxide-based contrast agents to improve vessel...
Combined free-running four-dimensional anatomical and flow magnetic resonance imaging with native contrast using Synchronization of Neighboring Acquisitions by Physiological Signals.
BACKGROUND
Four-dimensional (4D) flow magnetic resonance imaging (MRI) often relies on the injection of gadolinium- or iron-oxide-based contrast agents to improve vessel delineation. In this work, a novel technique is developed to acquire and reconstruct 4D flow data with excellent dynamic visualization of blood vessels but without the need for contrast injection. Synchronization of Neighboring Acquisitions by Physiological Signals (SyNAPS) uses pilot tone (PT) navigation to retrospectively synchronize the reconstruction of two free-running three-dimensional radial acquisitions, to create co-registered anatomy and flow images.
METHODS
Thirteen volunteers and two Marfan syndrome patients were scanned without contrast agent using one free-running fast interrupted steady-state (FISS) sequence and one free-running phase-contrast MRI (PC-MRI) sequence. PT signals spanning the two sequences were recorded for retrospective respiratory motion correction and cardiac binning. The magnitude and phase images reconstructed, respectively, from FISS and PC-MRI, were synchronized to create SyNAPS 4D flow datasets. Conventional two-dimensional (2D) flow data were acquired for reference in ascending (AAo) and descending aorta (DAo). The blood-to-myocardium contrast ratio, dynamic vessel area, net volume, and peak flow were used to compare SyNAPS 4D flow with Native 4D flow (without FISS information) and 2D flow. A score of 0-4 was given to each dataset by two blinded experts regarding the feasibility of performing vessel delineation.
RESULTS
Blood-to-myocardium contrast ratio for SyNAPS 4D flow magnitude images (1.5 ± 0.3) was significantly higher than for Native 4D flow (0.7 ± 0.1, p < 0.01) and was comparable to 2D flow (2.3 ± 0.9, p = 0.02). Image quality scores of SyNAPS 4D flow from the experts (M.P.: 1.9 ± 0.3, E.T.: 2.5 ± 0.5) were overall significantly higher than the scores from Native 4D flow (M.P.: 1.6 ± 0.6, p = 0.03, E.T.: 0.8 ± 0.4, p < 0.01) but still significantly lower than the scores from the reference 2D flow datasets (M.P.: 2.8 ± 0.4, p < 0.01, E.T.: 3.5 ± 0.7, p < 0.01). The Pearson correlation coefficient between the dynamic vessel area measured on SyNAPS 4D flow and that from 2D flow was 0.69 ± 0.24 for the AAo and 0.83 ± 0.10 for the DAo, whereas the Pearson correlation between Native 4D flow and 2D flow measurements was 0.12 ± 0.48 for the AAo and 0.08 ± 0.39 for the DAo. Linear correlations between SyNAPS 4D flow and 2D flow measurements of net volume (r = 0.83) and peak flow (r = 0.87) were larger than the correlations between Native 4D flow and 2D flow measurements of net volume (r = 0.79) and peak flow (r = 0.76).
CONCLUSION
The feasibility and utility of SyNAPS were demonstrated for joint whole-heart anatomical and flow MRI without requiring electrocardiography gating, respiratory navigators, or contrast agents. Using SyNAPS, a high-contrast anatomical imaging sequence can be used to improve 4D flow measurements that often suffer from poor delineation of vessel boundaries in the absence of contrast agents.
Topics: Humans; Predictive Value of Tests; Blood Flow Velocity; Adult; Image Interpretation, Computer-Assisted; Male; Regional Blood Flow; Marfan Syndrome; Female; Young Adult; Case-Control Studies; Magnetic Resonance Angiography; Reproducibility of Results; Feasibility Studies; Hemodynamics; Perfusion Imaging; Contrast Media; Time Factors; Middle Aged
PubMed: 38309581
DOI: 10.1016/j.jocmr.2024.101006 -
JOR Spine Mar 2024Marfan syndrome (MFS) is a rare genetic disorder caused by mutations in the Fibrillin-1 gene (FBN1) with significant clinical features in the skeletal, cardiopulmonary,...
BACKGROUND
Marfan syndrome (MFS) is a rare genetic disorder caused by mutations in the Fibrillin-1 gene (FBN1) with significant clinical features in the skeletal, cardiopulmonary, and ocular systems. To gain deeper insights into the contribution of epigenetics in the variability of phenotypes observed in MFS, we undertook the first analysis of integrating DNA methylation and gene expression profiles in whole blood from MFS and healthy controls (HCs).
METHODS
The Illumina 850K (EPIC) DNA methylation array was used to detect DNA methylation changes on peripheral blood samples of seven patients with MFS and five HCs. Associations between methylation levels and clinical features of MFS were analyzed. Subsequently, we conducted an integrated analysis of the outcomes of the transcriptome data to analyze the correlation between differentially methylated positions (DMPs) and differentially expressed genes (DEGs) and explore the potential role of methylation-regulated DEGs (MeDEGs) in MFS scoliosis. The weighted gene co-expression network analysis was used to find gene modules with the highest correlation coefficient with target MeDEGs to annotate their functions in MFS.
RESULTS
Our study identified 1253 DMPs annotated to 236 genes that were primarily associated with scoliosis, cardiomyopathy, and vital capacity. These conditions are typically associated with reduced lifespan in untreated MFS. We calculated correlations between DMPs and clinical features, such as cobb angle to evaluate scoliosis and FEV1% to assess pulmonary function. Notably, cg20223687 (PTPRN2) exhibited a positive correlation with cobb angle of scoliosis, potentially playing a role in ERKs inactivation.
CONCLUSIONS
Taken together, our systems-level approach sheds light on the contribution of epigenetics to MFS and offers a plausible explanation for the complex phenotypes that are linked to reduced lifespan in untreated MFS patients.
PubMed: 38304329
DOI: 10.1002/jsp2.1304 -
Frontiers in Cell and Developmental... 2023Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by gene. It serves as a structural component of microfibrils and... (Review)
Review
Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by gene. It serves as a structural component of microfibrils and provides force-bearing mechanical support in elastic and nonelastic connective tissue. As such, mutations in the gene can cause a wide variety of genetic diseases such as Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal and cardiovascular abnormalities. FBN1 also interacts with numerous microfibril-associated proteins, growth factors and cell membrane receptors, thereby mediating a wide range of biological processes such as cell survival, proliferation, migration and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. In this review, we summarize the structure and expression of FBN1 and present our current understanding of the functional role of FBN1 in various human diseases. This knowledge will allow to develop better strategies for therapeutic intervention of FBN1 related diseases.
PubMed: 38269088
DOI: 10.3389/fcell.2023.1302285 -
International Journal of Molecular... Jan 2024Thoracic aortic aneurysm (TAA) has a prevalence of 0.16-0.34% and an incidence of 7.6 per 100,000 person-years, accounting for 1-2% of all deaths in Western countries.... (Review)
Review
Thoracic aortic aneurysm (TAA) has a prevalence of 0.16-0.34% and an incidence of 7.6 per 100,000 person-years, accounting for 1-2% of all deaths in Western countries. Currently, no effective pharmacological therapies have been identified to slow TAA development and prevent TAA rupture. Large TAAs are treated with open surgical repair and less invasive thoracic endovascular aortic repair, both of which have high perioperative mortality risk. Therefore, there is an urgent medical need to identify the cellular and molecular mechanisms underlying TAA development and rupture to develop new therapies. In this review, we summarize animal TAA models including recent developments in porcine and zebrafish models: porcine models can assess new therapeutic devices or intervention strategies in a large mammal and zebrafish models can employ large-scale small-molecule suppressor screening in microwells. The second part of the review covers current views of TAA pathogenesis, derived from recent studies using these animal models, with a focus on the roles of the transforming growth factor-beta (TGFβ) pathway and the vascular smooth muscle cell (VSMC)-elastin-contractile unit. The last part discusses TAA treatment options as they emerge from recent preclinical studies.
Topics: Humans; Animals; Swine; Zebrafish; Aortic Aneurysm, Thoracic; Aortic Rupture; Models, Animal; Muscle Contraction; Mammals
PubMed: 38255976
DOI: 10.3390/ijms25020901 -
Journal of Clinical Laboratory Analysis Jan 2024Marfan syndrome (MFS), caused by pathogenic variants of FBN1 (fibrillin-1), is a systemic connective tissue disorder with variable phenotypes and treatment...
BACKGROUND
Marfan syndrome (MFS), caused by pathogenic variants of FBN1 (fibrillin-1), is a systemic connective tissue disorder with variable phenotypes and treatment responsiveness depending on the variant. However, a significant number of individuals with MFS remain genetically unexplained. In this study, we report novel pathogenic intronic variants in FBN1 in two unrelated families with MFS.
METHODS
We evaluated subjects with suspected MFS from two unrelated families using Sanger sequencing or multiplex ligation-dependent probe amplification of FBN1 and/or panel-based next-generation sequencing. As no pathogenic variants were identified, whole-genome sequencing was performed. Identified variants were analyzed by reverse transcription-PCR and targeted sequencing of FBN1 mRNA harvested from peripheral blood or skin fibroblasts obtained from affected probands.
RESULTS
We found causative deep intronic variants, c.6163+1484A>T and c.5788+36C>A, in FBN1. The splicing analysis revealed an insertion of in-frame or out-of-frame intronic sequences of the FBN1 transcript predicted to alter function of calcium-binding epidermal growth factor protein domain. Family members carrying c.6163+1484A>T had high systemic scores including prominent skeletal features and aortic dissection with lesser aortic dilatation. Family members carrying c.5788+36C>A had more severe aortic root dilatation without aortic dissection. Both families had ectopia lentis.
CONCLUSION
Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies. This study expands the mutation spectrum of FBN1 and points out the importance of intronic sequence analysis and the need for integrative functional studies in MFS diagnosis.
Topics: Humans; Fibrillin-1; Mutation; Marfan Syndrome; Genetic Testing; Aortic Dissection; Aortic Diseases; Adipokines
PubMed: 38234087
DOI: 10.1002/jcla.25009 -
Cureus Dec 2023This compelling case study unravels a tragic narrative of a 40-year-old male with Marfanoid habitus, navigating the intricate web of Marfan syndrome (MFS) and succumbing...
This compelling case study unravels a tragic narrative of a 40-year-old male with Marfanoid habitus, navigating the intricate web of Marfan syndrome (MFS) and succumbing to the devastating complications of aortic dissection. The patient's journey underscores the challenges in managing this rare connective tissue disorder, emphasizing the critical interplay between genetic predisposition and cardiovascular pathology. Moreover, the lack of immediate operative intervention due to the critical condition emphasizes the crucial need for timely diagnosis and intervention. The journey from genetic mutation to cardiovascular complications in MFS or related marfanoid habitus is complex and multifaceted. This case study aims to navigate this intricate path, emphasizing the need for a nuanced understanding of the underlying molecular and structural changes. Furthermore, it reinforces the critical role of ongoing cardiovascular monitoring and surgical interventions to prolong survival and enhance the quality of life for individuals grappling with the challenges posed by MFS or related habitus.
PubMed: 38229793
DOI: 10.7759/cureus.50651 -
Cureus Dec 2023Microspherophakia constitutes a rare, mostly bilateral anomaly of the crystalline lens, which is characterized by the presence of an increased lens thickness and reduced...
Microspherophakia constitutes a rare, mostly bilateral anomaly of the crystalline lens, which is characterized by the presence of an increased lens thickness and reduced equatorial diameter. It is frequently associated with lens subluxation, translating into a high degree of variable lenticular myopia and defective accommodation. The purpose of this report is to describe the treatment of a three-year-old female patient with microspherophakia, with the scleral fixation of an intraocular lens using the z-suture technique. A three-year-old female patient with Marfan Syndrome presented with high bilateral myopia and esotropia. Lens subluxation was perceived, and she was proposed for bilateral surgery. Scleral fixation of the intraocular lens was performed using the z-suture technique. During the five-year follow-up period, she maintained a best-corrected visual acuity of 20/20 in both eyes wearing bifocal glasses. Microspherophakia is a rare but impactful condition, frequently related to severe and variable refractive error due to the lens shape and zonule instability. Intraocular lens implantation in the capsular bag is usually impossible, and scleral fixation is a valid alternative. The z-suture technique avoids suture knots and the need for intrascleral flaps, reducing the risk of suture-related complications.
PubMed: 38222140
DOI: 10.7759/cureus.50445