scholarly journals Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease

2021 ◽  
Vol 11 (3) ◽  
pp. 132-138
Author(s):  
Shreyas A. Bhave ◽  
Dongchuan Guo ◽  
Stoyan N. Angelov ◽  
Michael J. Bamshad ◽  
Deborah A. Nickerson ◽  
...  
Keyword(s):  
Early Onset ◽  
Transforming Growth Factor ◽  
Vascular Malformations ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Vascular Events ◽  
Thoracic Aortic Disease ◽  
Pathogenic Potential ◽  
Aortic Dissections

Thoracic aortic aneurysms (TAAs) that progress to acute thoracic aortic dissections (TADs) are life-threatening vascular events that have been associated with altered transforming growth factor (TGF) β signaling. In addition to TAA, multiple genetic vascular disorders, including hereditary hemorrhagic telangiectasia (HHT), involve altered TGFβ signaling and vascular malformations. Due to the importance of TGFβ, genomic variant databases have been curated for activin receptor-like kinase 1 (ALK1) and endoglin (ENG). This case report details seven variants in SMAD4 that are associated with either heritable or early-onset aortic dissections and compares them to pathogenic exon variants in gnomAD v2.1.1. The TAA and TAD variants were identified through whole exome sequencing of 346 families with unrelated heritable thoracic aortic disease (HTAD) and 355 individuals with early-onset (age ≤ 56 years old) thoracic aortic dissection (ESTAD). An allele frequency filter of less than 0.05% was applied in the Genome Aggregation Database (gnomAD exome v2.1.1) with a combined annotation-dependent depletion score (CADD) greater than 20. These seven variants also have a higher REVEL score (>0.2), indicating pathogenic potential. Further in vivo and in vitro analysis is needed to evaluate how these variants affect SMAD4 mRNA stability and protein activity in association with thoracic aortic disease.

Abstract 15169: De Novo Variants of USP10 in Early Onset Bicuspid Aortic Valve Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Siddharth K Prakash ◽  
Angela T Yetman ◽  
Hector I Michelena ◽  
Malenka M Bissell ◽  
Yuli Y Kim ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Early Onset ◽  
Rare Variants ◽  
De Novo ◽  
Late Onset ◽  
Copy Number Variants ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Dissections

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) < 1%, Combined Annotation Dependent Depletion (CADD) scores > 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) > 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF<5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium

2019 ◽  
Vol 56 (4) ◽  
pp. 252-260 ◽  
Author(s):  
Ellen M Hostetler ◽  
Ellen S Regalado ◽  
Dong-Chuan Guo ◽  
Nadine Hanna ◽  
Pauline Arnaud ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Cumulative Risk ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Disease ◽  
Thoracic Aortic Aneurysms ◽  
Missense Variants ◽  
Variant Type ◽  
Pathogenic Variants ◽  
Reduced Penetrance

BackgroundPathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants.MethodsAortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.ResultsAortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.ConclusionsSMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.

scholarly journals Transforming Growth Factor Beta3 is Required for Cardiovascular Development

2020 ◽  
Vol 7 (2) ◽  
pp. 19 ◽  
Author(s):  
Mrinmay Chakrabarti ◽  
Nadia Al-Sammarraie ◽  
Mengistu G. Gebere ◽  
Aniket Bhattacharya ◽  
Sunita Chopra ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Collagen Matrix ◽  
Ventricular Myocardium ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Aortic Aneurysms ◽  
Cardiovascular Development ◽  
Transforming Growth Factor Beta3

Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3−/− fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3−/− fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3−/− fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGFβ3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGFβ3 was required for collagen matrix reorganization. Biochemical studies indicated the ‘paradoxically’ increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGFβ3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGFβ signaling pathways.

Endovascular Repair of the Descending Thoracic Aorta: Evidence for the Change in Clinical Practice

Vascular ◽  
2005 ◽  
Vol 13 (3) ◽  
pp. 148-157 ◽  
Author(s):  
Saiqa Sayed ◽  
Matt M. Thompson
Keyword(s):  
Thoracic Aorta ◽  
Endovascular Repair ◽  
Graft Infection ◽  
Aortic Disease ◽  
Outcome Data ◽  
Aortic Aneurysms ◽  
Descending Thoracic Aorta ◽  
Thoracic Aortic Disease ◽  
Technical Success Rate ◽  
Open Conversion

The purpose was to review outcome data following endovascular repair of the descending thoracic aorta from reports published between 1994 and 2004. To accomplish this task, 1,518 patients underwent endovascular repair for thoracic aortic disease; 810 thoracic aortic aneurysms, 500 type B thoracic aortic dissections, and 106 traumatic ruptures. The 30-day mortality rate was 5.5% and 6% for late postoperative deaths. The primary technical success rate was 97%, with only 15 patients requiring open conversion. Neurologic deficits occurred in 29 patients. In total, 118 endoleaks were reported; 29 were restented, and the remainder required surgical intervention. Graft infection occurred in 6 cases, and migrations were detected in 10. The conclusion reached is that endovascular repair of descending thoracic aortic disease is feasible and can be achieved with low rates of perioperative morbidity and mortality. As few long-term data exist on the durability of thoracic stent grafts, lifelong surveillance remains necessary.

Thoracic aortic aneurysms and other conditions

2016 ◽  
Author(s):  
Demosthenes G. Katritsis ◽  
Bernard J. Gersh ◽  
A. John Camm
Keyword(s):  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Disease ◽  
Thoracic Aortic Aneurysms

Thoracic aortic aneurysms, aortic atheroembolic disease, and other cardiovascular conditions associated with thoracic aortic disease are discussed.

scholarly journals Screening for Familial Thoracic Aortic Aneurysms with Aortic Imaging Does Not Detect All Potential Carriers of the Disease

Aorta ◽  
2015 ◽  
Vol 03 (01) ◽  
pp. 1-8 ◽  
Author(s):  
Matias Hannuksela ◽  
Eva-Lena Stattin ◽  
Bengt Johansson ◽  
Bo Carlberg
Keyword(s):  
Thoracic Aorta ◽  
Autosomal Dominant ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Aortic Dilatation ◽  
Expected Number ◽  
Thoracic Aortic Disease ◽  
First Degree Relatives ◽  
Number Of Individuals ◽  
Second Degree

Background: About 20% of patients with thoracic aortic aneurysm or dissection (TAAD) have a first-degree relative with a similar disease. The familial form (FTAAD) of the disease is inherited in an autosomal-dominant pattern. Current guidelines for thoracic aortic disease recommend screening of first-degree relatives of TAAD patients. In known familial disease, screening of both first- and second-degree relatives is recommended. However, the outcomes of such a screening program are unknown. Methods: We screened all first- and second-degree relatives in seven families with known FTAAD with echocardiography. No underlying gene defect had been detected in these families. Results: Of 119 persons investigated, 13 had known thoracic aortic disease. In the remaining 106 cases, we diagnosed 19 additional individuals with a dilated ascending thoracic aorta; for an autosomal-dominant disease, the expected number of individuals in this group would have been 40 (p<0.0001). Further, only one of the 20 first-degree relatives younger than 40 years had a dilated aorta, although the expected number of individuals with a disease-causing mutation would have been 10. Conclusions: In most families with TAAD, a diagnosis still relies on measuring the diameter of the thoracic aorta. We show that a substantial number of previously unknown cases of aortic dilatation can be identified by screening family members. It is, however, not possible to consider anyone free of the condition, even if the aortic diameter is normal, especially at a younger age.

scholarly journals ABO blood group and the risk of aortic disease: a nationwide cohort study

BMJ Open ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. e036040
Author(s):  
Igor Zindovic ◽  
Gustaf Edgren ◽  
Shahab Nozohoor ◽  
Ammar Majeed
Keyword(s):  
Blood Group ◽  
Blood Donors ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Secondary Outcome ◽  
Abo Blood Group ◽  
Patient Cohort ◽  
Using Data ◽  
Group B ◽  
Aortic Dissections

ObjectivesTo analyse the association between ABO blood group and aortic disease using data on blood donors and transfused patients from Sweden.DesignThis was a retrospective study using data from the Swedish portion of the Scandinavian Donations and Transfusions Database. The association between ABO blood group and aortic disease was analysed using log-linear Poisson regression models and presented as incidence rate ratios (IRRs).SettingSwedish population-based study.ParticipantsThe study cohort consisted of 1 164 561 Swedish blood donors and 961 637 transfused patients with a combined follow-up time of 29 390 649 person-years.Primary and secondary outcome measuresIRRs of aortic events (ie, aortic aneurysms and/or aortic dissections) in relation to patient blood group.ResultsA total of 20 684 aortic events occurred during the study period. Non-O donors and patients had similar incidence of aortic events when compared with blood group O donors and patients with an IRR of 0.98 (95% CI, 0.93–1.04) and 1.00 (95% CI, 0.97–1.03), respectively. There were no differences between non-O and blood group O individuals when aortic dissections and aortic aneurysms were analysed separately. Blood group B conferred a lower risk of aortic aneurysms in the patient cohort when compared with blood group O (IRR, 0.90; 95% CI, 0.85–0.96).ConclusionsIn the present study, there were no statistically significant associations between ABO blood group and the risk of aortic disease. A possible protective effect of blood group B was observed in the patient cohort but this finding requires further investigation.

scholarly journals Rare deleterious variants of NOTCH1 , GATA4 , SMAD6 , and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease

2020 ◽  
Vol 8 (10) ◽  
Author(s):  
Fadi I. Musfee ◽  
Dongchuan Guo ◽  
Amélie C. Pinard ◽  
Ellen M. Hostetler ◽  
Elizabeth E. Blue ◽  
...  
Keyword(s):  
Early Onset ◽  
Aortic Disease ◽  
Thoracic Aortic Disease

Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: Do we need genetics for clinical decisions?

VASA ◽  
2010 ◽  
Vol 39 (1) ◽  
pp. 17-32 ◽  
Author(s):  
von Kodolitsch ◽  
Rybczynski ◽  
Bernhardt ◽  
Mir ◽  
Treede ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Autosomal Dominant ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Clinical Implications ◽  
Thoracic Aortic Disease ◽  
Gene Coding ◽  
Autosomal Dominant Fashion ◽  
Fibrillin 1 ◽  
Work Up

Marfan syndrome (MFS) is a disorder of the connective tissue that is inherited in an autosomal dominant fashion and that is classically caused by mutations in the gene coding for fibrillin-1, FBN1. The high mortality of untreated MFS results almost exclusively from aortic complications such as aortic dissection and rupture. However, more than half of patients with Marfan-like features do not have MFS, but have other diseases including inherited aortic aneurysms and dissections (TAAD). We elucidate the increasing spectrum of syndromes associated with Marfan-like features and discuss the clinical implications of these diseases. We performed a systematic review to tabulate all known inherited diseases and syndromes carrying a risk for thoracic aortic disease. We discuss evidence that different syndromes with different causative genes and mutations have different prognoses and profiles of cardiovascular manifestations. We conclude that future decisions for optimized management of patients with inherited TAAD require a comprehensive clinical and genetic work-up.

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