Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An ...evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.
The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework.
We applied the semiquantitative ClinGen framework to assess presumed gene–disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel.
Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as “HTAAD genes” (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD.
The ClinGen framework is useful to semiquantitatively assess the strength of gene–disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.
Marfan syndrome Milewicz, Dianna M; Braverman, Alan C; De Backer, Julie ...
Nature reviews. Disease primers,
09/2021, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in ...FBN1, which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection.
Thoracic aortic dilatation requires accurate and timely detection to prevent progression to thoracic aortic aneurysm and aortic dissection. The detection of thoracic aortic dilatation necessitates ...the availability of cut-off values for normal aortic diameters. Tools to evaluate aortic dimension above the root are scarce and inconsistent regarding age groups. The aim of this study was to provide reference values for aortic root and ascending aortic diameters on the basis of transthoracic echocardiographic measurements in a large cohort of children and adults. Diameters at the level of the sinuses of Valsalva (SoV) and ascending aorta (AA) were assessed with transthoracic echocardiography in 849 subjects (453 females, age range 1 to 85 years, mean 40.1 ± 21.3 years) and measured according to published guidelines. Linear regression analysis was applied to create nomograms, as well as equations for upper limits of normal and z-scores. SoV and AA diameters were strongly correlated with age, body surface area (BSA), and weight (r = 0.67 to 0.79, p <0.001 for all). Male subjects had significantly larger aortic dimensions at all levels in adulthood, even after BSA correction (p ≤0.004 for all age intervals). Gender-, age-, and BSA-specific upper limits of normal and z-score equations were developed from a multivariate regression model, which strongly predicts SoV and AA diameters (adjusted R2 for SoV = 0.84 and 0.67 and for AA = 0.82 and 0.74, for male and female subjects, respectively). In conclusion, this study provides widely applicable reference values for thoracic aortic dilatation screening purposes. Age, BSA, and gender must be taken into account when assessing an individual patient.
The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and ...aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively).
We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome.
We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome.
Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.
Improvements in surgery have resulted in more women with repaired congenital heart disease (CHD) surviving to adulthood. Women with CHD, who wish to embark on pregnancy require prepregnancy ...counselling. This consultation should cover several issues such as the long-term prognosis of the mother, fertility and miscarriage rates, recurrence risk of CHD in the baby, drug therapy during pregnancy, estimated maternal risk and outcome, expected fetal outcomes and plans for pregnancy. Prenatal genetic testing is available for those patients with an identified genetic defect using pregestational diagnosis or prenatal diagnosis chorionic villus sampling or amniocentesis. Centralisation of care is needed for high-risk patients. Finally, currently there are no recommendations addressing the issue of the delivery. It is crucial that a dedicated plan for delivery should be available for all cardiac patients. The maternal mortality in low-income to middle-income countries is 14 times higher than in high-income countries and needs additional aspects and dedicated care.
Angiotensin receptor blockers (ARBs) and β blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this ...condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments.
In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus β blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus β blocker; and indirectly, β blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva.
We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 SE 0·02 ARB vs 0·13 SE 0·02 control; absolute difference –0·07 95% CI –0·12 to –0·01; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with β-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with β blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase –0·08 SE 0·03 in ARB groups vs –0·11 SE 0·02 in β-blocker groups; absolute difference 0·03 95% CI –0·05 to 0·10; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between β blockers and control was –0·09 (95% CI –0·18 to 0·00; p=0·042).
In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a β blocker. The effects of β blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and β blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery.
Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.
To investigate the anterior scleral thickness (AST) in patients with Marfan syndrome (MFS).
A prospective, cross-sectional study was conducted at the Department of Ophthalmology, Ghent University ...Hospital, Ghent, including patients with a genetically confirmed clinical diagnosis of MFS and age-, gender- and axial length-matched controls. Subjects with known corneal, conjunctival or scleral pathology and a history of ocular surgery, including pars plana vitrectomy, recent contact lens use or high-grade astigmatism were excluded. Subjects underwent non-cycloplegic autorefraction, Scheimpflug-based corneal tomography, axial length measurement and spectral-domain optical coherence tomography (OCT). AST was manually measured at 1 mm (AST1), 2 mm (AST2) and 3 mm (AST3) from the scleral spur, temporally and nasally.
A total of 56 subjects (28 subjects in the MFS group and 28 matched subjects in the control group) were included in this study. In patients with MFS, AST was significantly reduced compared to matched controls, both overall and at every analysed measuring point in the nasal and temporal areas (p < 0.001). Central corneal thickness (CCT) and mean keratometry (Kmean) values were significantly lower in patients with MFS (p < 0.05). A positive correlation was found between nasal AST and CCT in patients with MFS. No correlation was found between AST and Kmean or between AST and axial length. In patients with MFS with ectopia lentis, compared to those without, temporal AST3 was significantly lower (p < 0.05). AST was significantly lower in patients with MFS harbouring a variant predicted to cause haploinsufficiency compared to those with a variant expected to lead to a dominant negative effect for both nasal and temporal measurements.
Based on anterior segment OCT measurements, AST of patients with MFS is significantly lower compared to matched controls.
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.
Sex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these ...observations are largely unknown.
In an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17β-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts.
Our small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non-pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17β-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells.
Pregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect.
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