Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection

Renard, Marjolijn; Francis, Catherine; Ghosh, Rajarshi; Scott, Alan F.; Witmer, P. Dane; Adès, Lesley C.; Andelfinger, Grégor; Arnaud, Pauline; Boileau, Cathérine; Callewaert, Bert; Guo, Dongchuan; Hanna, Nadine; Lindsay, Mark E.; Morisaki, Hiroko; Morisaki, Takayuki; Pachter, Nicholas; Robert, Leema; Laer, Lut Van; Dietz, Harry C.; Loeys, Bart; Milewicz, Dianna M.; Backer, Julie De

doi:10.1016/j.jacc.2018.04.089

Cited by 223 publications

(221 citation statements)

References 34 publications

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“…In summary, diagnostic accuracy to identify HTAAD and type of HTAAD is important for the development of personalized clinical care. Use of genes with high evidence of gene‐disease association and clinical validity—defined by the accuracy for which identifying the pathogenic variant in a gene confers predisposition for or diagnosis of a specific clinical condition (Renard et al, )—can be instrumental in differentiating diseases with significant phenotypic overlap such as MFS, LDS and SGS and varied severity of aortic disease. The differentiation may help guide management and risk stratification.…”

Section: Genetic Testingmentioning

confidence: 99%

“…In a recent classification analysis by Renard et al, 53 HTAAD gene-disease pairs were curated by an expert team. Only 11 genes (ACTA2, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK, LOX, PRKG1) were deemed to have "Definitive" or "Strong" gene-disease association (Renard et al, 2018 In summary, diagnostic accuracy to identify HTAAD and type of HTAAD is important for the development of personalized clinical care.…”

Section: Genetic Testingmentioning

confidence: 99%

“…Unlike AAA, many forms of TAAD are attributed to genetic variation in a single gene. In fact, identifying the genetic basis for hereditary thoracic aortic aneurysm and dissection (HTAAD), has a significant role in determining aneurysm and dissection risk and subsequent management (Renard et al, ).…”

Section: Introductionmentioning

confidence: 99%

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The genetics of aortopathies: Hereditary thoracic aortic aneurysms and dissections

Chou

Lindsay

2020

American J of Med Genetics Pt C

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Aortopathies encompass a variety of inherited and acquired pathologies that increase risk of life‐threatening dissection or rupture. Identifying individuals with hereditary thoracic aortic aneurysm and dissection (HTAAD) for longitudinal monitoring, medical therapy, or elective and preventative repair is paramount to reduce risk of cardiovascular‐related mortality and complications from dissection and rupture. Over the past couple of decades, pathogenic variants in numerous genes have been identified in relation to HTAAD. The genetic diagnosis can help stratify patient risk and provide guidance on medical treatment, timing of prophylactic surgical repair, as well as longitudinal surveillance and imaging. Implicated genes and their associated proteins have been found to act on a diverse variety of pathways, cells and structural components linked to transforming growth factor beta (TGF‐β) signaling pathways, disruption of the vascular smooth muscle cell contractile apparatus, and primary disruption of extracellular matrix homeostasis. This review describes relevant genetic variants that may help identify and guide the management of hereditary thoracic aortic aneurysms and dissections.

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Section: Genetic Testingmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

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The genetics of aortopathies: Hereditary thoracic aortic aneurysms and dissections

Chou

Lindsay

2020

American J of Med Genetics Pt C

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“…Thoracic aortic dissection is a life-threatening condition, responsible for 15,000 deaths a year in the United States. 1 Up to 25% of patients presenting with a thoracic aortic aneurysm and dissection have an underlying genetic predisposition, 2, 3 which can be associated with syndromic features, such as Marfan syndrome or Loeys-Dietz syndrome, or not associated with syndromic features, as with PRKG1 and MYH11 mutations. 4 Variants in many genes, including FBN1, ACTA2 and SMAD3 , among others, can lead to either syndromic or non-syndromic thoracic aortic aneurysm and dissection.…”

Section: Introductionmentioning

confidence: 99%

“…5 Recent advances in the field have shown definitive and strong evidence to support the role of pathogenic variants in ACTA2, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK, LOX , and PRKG1 5 as predisposing to hereditary thoracic aortic disease. 3…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

Wolford

2018

Preprint

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1Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine 2 screening for genetic variants causing thoracic aortic dissection is not currently performed for 3 patients or their family members. 4 Methods:We performed whole exome sequencing of 240 patients with thoracic aortic dissection 5 (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-6 control status, we annotated variants in 11 genes for pathogenicity. 7Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, 8 TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. 9Among dissection cases, we compared those with pathogenic variants to those without and found 10 that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher 11 rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking 12 (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic 13 regression showed significant risk factors associated with pathogenic variants are age <50 [odds 14 ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and 15 family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 16 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7). 17 Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should 18 be considered in patients with aortic dissection, followed by cascade screening of family 19 members, especially in patients with age-of-onset of aortic dissection <50 years old, family 20 history of aortic disease, and no history of hypertension. 21 22 23 Keywords: thoracic aortic dissection, aortic rupture, gene sequencing, precision health 24 Dianna M. Milewicz (Dianna.M.Milewicz@uth.tmc.edu) has no conflicts of interest to disclose. 1 Cristen J. Willer (cristen@med.umich.edu) has no conflicts of interest to disclose. 2 Bo Yang (boya@med.umich.edu) has no conflicts of interest to disclose. 3 4 AUTHORS 5

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Development of a Prediction Model for Ascending Aortic Diameter Among Asymptomatic Individuals

Lin

Khurshid

Nekoui

et al. 2022

JAMA

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ImportanceAscending thoracic aortic disease is an important cause of sudden death in the US, yet most aortic aneurysms are identified incidentally.ObjectiveTo develop and validate a clinical score to estimate ascending aortic diameter.Design, Setting, and ParticipantsUsing an ongoing magnetic resonance imaging substudy of the UK Biobank cohort study, which had enrolled participants from 2006 through 2010, score derivation was performed in 30 018 participants and internal validation in an additional 6681. External validation was performed in 1367 participants from the Framingham Heart Study (FHS) offspring cohort who had undergone computed tomography from 2002 through 2005, and in 50 768 individuals who had undergone transthoracic echocardiography in the Community Care Cohort Project, a retrospective hospital-based cohort of longitudinal primary care patients in the Mass General Brigham (MGB) network between 2001-2018.ExposuresDemographic and clinical variables (11 covariates that would not independently prompt thoracic imaging).Main Outcomes and MeasuresAscending aortic diameter was modeled with hierarchical group least absolute shrinkage and selection operator (LASSO) regression. Correlation between estimated and measured diameter and performance for identifying diameter 4.0 cm or greater were assessed.ResultsThe 30 018-participant training cohort (52% women), were a median age of 65.1 years (IQR, 58.6-70.6 years). The mean (SD) ascending aortic diameter was 3.04 (0.31) cm for women and 3.32 (0.34) cm for men. A score to estimate ascending aortic diameter explained 28.2% of the variance in aortic diameter in the UK Biobank validation cohort (95% CI, 26.4%-30.0%), 30.8% in the FHS cohort (95% CI, 26.8%-34.9%), and 32.6% in the MGB cohort (95% CI, 31.9%-33.2%). For detecting individuals with an ascending aortic diameter of 4 cm or greater, the score had an area under the receiver operator characteristic curve of 0.770 (95% CI, 0.737-0.803) in the UK Biobank, 0.813 (95% CI, 0.772-0.854) in the FHS, and 0.766 (95% CI, 0.757-0.774) in the MGB cohorts, although the model significantly overestimated or underestimated aortic diameter in external validation. Using a fixed-score threshold of 3.537, 9.7 people in UK Biobank, 1.8 in the FHS, and 4.6 in the MGB cohorts would need imaging to confirm 1 individual with an ascending aortic diameter of 4 cm or greater. The sensitivity at that threshold was 8.9% in the UK Biobank, 11.3% in the FHS, and 18.8% in the MGB cohorts, with specificities of 98.1%, 99.2%, and 96.2%, respectively.Conclusions and RelevanceA prediction model based on common clinically available data was derived and validated to predict ascending aortic diameter. Further research is needed to optimize the prediction model and to determine whether its use is associated with improved outcomes.

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Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection

Cited by 223 publications

References 34 publications

The genetics of aortopathies: Hereditary thoracic aortic aneurysms and dissections

The genetics of aortopathies: Hereditary thoracic aortic aneurysms and dissections

Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

Development of a Prediction Model for Ascending Aortic Diameter Among Asymptomatic Individuals

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