Explore the vast range of titles available.

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. In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype–phenotype correlations. 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. 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.

Introduction The international recommendations tend to avoid physical activity (PA) for patients with Marfan syndrome (MFS). However, exceptions have recently been made in the most recent recommendations for these patients, suggesting benefits from doing PA at low intensity only. Furthermore, there is no evidence that moderate aerobic or weight training can worsen the disease symptoms and increase mortality of MFS patients. The present review sums up the work carried out in the field of PA and MFS. The review aims to (1) identify the different types of exercise testing and training protocols and (2) discuss the feasibility and potentially beneficial nature of PA as an innovative way to manage MFS patients. Methods The scientific literature was reviewed using the following words: Marfan syndrome, training, physical activity, evaluation, weight training, arterial disease, aneurysms, lung damage, aortic dissection, rupture. A total of 345 studies were prospected and 43 studies were included. Conclusions A limited number of studies were done in humans, however one demonstrated the feasibility of the management of MFS patients with PA. There were potential beneficial effects of PA on arterial structures, but this review also showed deleterious effects when PA was conducted at high intensities, corresponding to 75–85% of the maximal oxygen uptake. However, these effects have only been reported in animal studies.

Background Fatigue is often reported by individuals with Marfan syndrome (MFS). However, the determinants of fatigue and its impact on the daily lives of patients with MFS remain poorly understood. We sought to assess the level of fatigue and its determinants in individuals with MFS. Methods We conducted a cross-sectional study in ComPaRe Marfan, an e-cohort of MFS patients. Fatigue was assessed using the FACIT questionnaire already used in a wide range of chronic diseases. Pain and its interference with daily life were assessed using the Brief Pain Inventory. We performed univariate and multivariable linear regressions to identify determinants of fatigue. Results A total of 162 people with MFS completed the FACIT-Fatigue questionnaire. The median age was 46 and 59% were women. The median FACIT-Fatigue score was 31(IQR 22–39) and over ¾ of the cohort had a FACIT-Fatigue score below 40 corresponding to at least some level of fatigue. In the multivariate model, only pain interference was associated with fatigue (Coeff= -0.34, CI95%: [-0.46; -0.22], p  < 0.001). Beta-blocker treatment, history of aortic, lens or scoliosis surgery were not associated with FACIT fatigue score. In addition, the FACIT fatigue scores was repeated every month during 3 months and were stable over time. Conclusion Fatigue is common in patients with MFS and is associated with pain that interferes with daily life. Therefore, pain management in MFS patients could improve quality of life and fatigue.

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.

Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.

Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.

BackgroundIdentifying significant coronary artery disease (CAD) in patients with reduced left ventricular ejection fraction (rLVEF) is essential for guiding therapeutic decisions, including medical management, device implantation and potential revascularisation. Prior studies suggested that rest cardiac MRI (CMR) with late gadolinium enhancement (LGE) could reliably detect significant CAD. We aimed to evaluate the diagnostic accuracy of rest LGE-CMR for predicting significant CAD in rLVEF patients.MethodsIn this prospective, multicentre cohort study across 10 centres, adults with new-onset rLVEF≤45% without obvious cause were included. All patients underwent rest CMR and coronary angiography. Independent, blinded committees reviewed images. Significant CAD was defined as ≥70% stenosis in major coronary arteries. Ischaemic scars were identified on CMR as subendocardial LGE. The primary outcome was the sensitivity of CMR in detecting significant CAD.ResultsAmong 380 patients (median age 63 years, 68% male), significant CAD was present in 49 (13%). CMR identified ischaemic scars in 106 (28%). The sensitivity of CMR for detecting significant CAD was 57% (95% CI: 43% to 71%), specificity 76% (95% CI: 72% to 81%), positive predictive value 26% (95% CI: 18% to 35%) and negative predictive value 92% (95% CI: 89% to 95%). A CMR-first strategy would have missed 43% of significant CAD cases, many requiring revascularisation (86% of missed cases).ConclusionsIn this large, prospective multicentre study with independent image review, rest LGE-CMR demonstrated limited sensitivity for detecting significant CAD in patients with rLVEF. Relying solely on CMR could lead to missed diagnoses and undertreatment. CMR should be integrated with other diagnostic tools to optimise care in this population.Trial registration number NCT03231189.

Aims To report aortic events in a large family carrying a variant in the TGFBR2 gene. Methods Since 1990 up to 2024, we have conducted a longitudinal clinical study of a large single family comprising 63 members across four generations who carry the same TGFBR2 pathogenic variant. We assessed the incidence of aortic events and prophylactic surgery, as well as life expectancy. Results Over a follow-up, 21 patients died (33% of the population), of whom ten were related to a dissection (48%). Eight patients underwent prophylactic aortic root surgery (13%). Over the generations, there is an increase in life expectancy and a decrease in the likelihood of aortic dissection (p < 0.001), but no significant change in the combined endpoint of surgery, aortic dissection or death (p = 0.168). The type of prophylactic surgery has also evolved over the years from mechanical Bentall surgery to valve-sparing surgery. The variability in the age at onset of aortic events reflects the broad phenotypic spectrum of aortic disease associated with this variant. Conclusion Across four generations, improved diagnosis, prophylactic surgery, and surgical techniques were associated with reduced dissection rates and increased survival, despite marked intra-familial variability in aortic disease severity among carriers of the same TGFBR2 pathogenic variant.”

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

We aimed to assess the incidence and evolution of left ventricular (LV) thrombi in a high-risk population of patients with LV systolic dysfunction after anterior myocardial infarction (ant-MI). We also compared the accuracy of transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging with contrast-delayed enhancement (CMR-DE) in detecting LV thrombi. We prospectively included 100 consecutive patients with LV ejection fraction (LVEF) <45% at the first TTE performed <7 days after ant-MI. A second evaluation with TTE and CMR-DE (by blinded examiners) was performed at 30 days. A third TTE and assessment of clinical status were performed between 6 and 12 months after ant-MI. Patients (males 71%; mean age 59.1 ± 12.1 years; mean LVEF 33.5% ± 6.0%) were included at a median of 5.5 days (interquartile range 25th-75th percentile 4.25-6.0 days) after ant-MI. Thrombi were detected among 26 (26%) patients at a median of 12.0 days after ant-MI (7 patients at 1-7 days after MI; 15 at 8-30 days; and 4 after day 30). Sensitivity and specificity for LV thrombi detection were 94.7% and 98.5%, respectively, for TTE as compared with CMR-DE. Most thrombi (n = 24; 92.3%) disappeared after triple antithrombotic therapy (vitamin K antagonist in addition to dual antiplatelet therapy). Left ventricular thrombus is a frequent complication after ant-MI with systolic dysfunction. When a search for thrombus is prespecified, the accuracy of TTE is high as compared with CMR-DE. The best antithrombotic strategy is not known.