Pathogenetic Basis of Aortopathy and Aortic Valve Disease (TAA)

The main purpose of this study is to define the complex genetic and pathogenic basis of thoracic aortic aneurysm (TAA) and other forms of aortopathy and/or aortic valve disease by identifying novel disease-causing genes and by identifying important genetic modifiers for aortic and aortic valve disease severity.

Study Overview

• Status: Active, not recruiting
• Conditions: Aortic Valve Disease; Marfan Syndrome; Bicuspid Aortic Valve; Thoracic Aortic Aneurysm; Thoracic Aortic Dissection; Turner Syndrome; Vascular Ehlers-Danlos Syndrome; Familial Thoracic Aortic Aneurysm and Aortic Dissection; PHACE Syndrome; Aortopathies; Thoracic Aortic Disease; Thoracic Aortic Rupture; Ascending Aortic Disease; Descending Aortic Disease; Ascending Aortic Aneurysm; Descending Aortic Aneurysm; Loeys-Dietz Syndrome; Shprintzen-Goldberg Syndrome; Autosomal Recessive Cutis Laxa; Congenital Contractural Arachnodactyly; Arterial Tortuosity Syndrome; Bicuspid Aortic Valve-Associated Aortopathy

Detailed Description

Thoracic aortic aneurysm (TAA) is a type of aortopathy describing dilation of the proximal aortic dimensions including the aortic root, which is a risk factor for aortic dissection and sudden cardiac death. TAA and other forms of aortopathy (e.g. aortic tortuosity or aortic hypoplasia/stenosis) develop in the presence or absence of additional cardiovascular malformations including bicuspid aortic valve. TAA is associated with connective tissue disorders (e.g. Marfan syndrome), and familial clustering has been identified in a significant proportion of nonsyndromic cases, establishing high heritability. Pedigree analysis of TAA kindreds clearly identifies complex inheritance; however, progress towards understanding the genetic basis of TAA and other forms of aortopathy and, ultimately, the susceptibility to aortic dissection remains incomplete. There is a clinical need to develop novel methods for predicting disease risk based on genotype and phenotype, to further elucidate the genetic and pathogenic mechanisms of aortopathy, and to improve medical and surgical therapies. The overarching hypothesis of this study is that individual genetic variation modulates susceptibility to disease severity and progression. The goals of this study are 1) to ascertain a cohort of subjects who have aortopathy and/or aortic valve disease including TAA or who have genetic risk for the development of aortopathy and/or aortic valve disease, 2) to collect paired blood and tissue samples from well-characterized subjects, family members of subjects, and controls to perform genome-wide DNA sequence, histopathologic, transcriptional, and proteomic analyses, and 3) to establish a tissue biorepository with detailed phenotype information to facilitate a broad spectrum of current and future studies.

• Study Type: Observational
• Enrollment (Estimated): 3000

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Childrens Healthcare of Atlanta
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • IU School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Families affected by aortopathy, aortic valve disease, or syndromic or genetic diagnosis that poses risk for the development of aortic disease who have not yet developed disease.

Description

Inclusion Criteria:

• Open to external enrollment:

  • Subjects with a genetic diagnosis of Marfan Syndrome (MDS), Loeys-Dietz Syndrome (LDS), or Vascular Ehlers-Danlos Syndrome (EDS); (Positive genetic testing or a previous cardiac study required to be eligible)
  • Family members of eligible subjects (Only family members of subjects with syndromic diagnoses are eligible for external enrollment at this time)

• Closed to external enrollment:

  • Subjects with aortic disease including TAA* or dissection, aortic tortuosity, or aortic hypoplasia/stenosis (based on any cardiac imaging modality including echocardiography, CT, MRI, or angiography)
  • Subjects with aortic valve disease (bicuspid, unicuspid, or tricuspid disease)
  • Control subjects having tissue removed during a surgical procedure (e.g. coronary artery bypass graft surgery (CABG), cardiac transplant, etc.)

Exclusion Criteria:

• Inability or unwillingness to provide consent (assent when indicated)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort
Aortopathy- Closed to external enrollment; Subjects with aortic disease including TAA or dissection, aortic tortuosity, or aortic hypoplasia/stenosis (based on any cardiac imaging modality including echocardiography, CT, MRI, or angiography)
Syndromic- Open to external enrollment; Subjects with a genetic diagnosis of Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS), Vascular Ehlers-Danlos Syndrome (EDS) •positive genetic testing and/or a previous cardiac study required to be eligible
Aortopathy with Positive Genetic Results- Open to Enrollment; Subjects with aortic disease including TAA or dissection, aortic tortuosity, or aortic hypoplasia/stenosis (based on any cardiac imaging modality including echocardiography, CT, MRI, or angiography) who also have positive genetic testing results related to aortopathy.
Aortic Valve Disease- Closed to enrollment; Subjects with aortic valve disease (bicuspid, unicuspid, or tricuspid disease)
Family Members- Open to external enrollment; Family members of eligible subjects •Only family members of subjects with syndromic diagnoses are eligible for external enrollment at this time
Controls- Closed to external enrollment; Control subjects having tissue removed during a surgical procedure (e.g. coronary artery bypass graft surgery (CABG), cardiac transplant, etc.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biorepository Establishment	Establish a biorepository with detailed phenotype information to facilitate a broad spectrum of current and future studies	20 years
Genetic Analysis	The mechanisms of TAA pathogenesis will be determined by studying explanted aortic tissue and cells derived from patients with TAA for gene expression, protein expression, and other functional assays.	20 years

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Benjamin Landis, MD, Yale University

Study record dates

Study Major Dates

• Study Start: December 10, 2015
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: October 6, 2017
• First Submitted That Met QC Criteria: February 19, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Actual): February 13, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Cardiac Disease; Cardiovascular Genetics
• Additional Relevant MeSH Terms: Urogenital Diseases; Dissection, Blood Vessel; Acute Aortic Syndrome; Endocrine System Diseases; Bone Diseases; Musculoskeletal Diseases; Vascular Diseases; Cardiovascular Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Connective Tissue Diseases; Hematologic Diseases; Heart Valve Diseases; Gonadal Disorders; Skin Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Abnormalities, Multiple; Hemostatic Disorders; Hemorrhagic Disorders; Skin Diseases, Genetic; Skin Abnormalities; Disorders of Sex Development; Urogenital Abnormalities; Aortic Diseases; Sex Chromosome Disorders; Chromosome Disorders; Bone Diseases, Developmental; Aneurysm; Collagen Diseases; Aortic Aneurysm; Aortic Dissection; Sex Chromosome Disorders of Sex Development; Gonadal Dysgenesis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Ehlers-Danlos Syndrome; Aortic Valve Disease; Bicuspid Aortic Valve Disease; Dissection, Thoracic Aorta; Ehlers-Danlos Syndrome, Type IV; Aneurysm, Ascending Aorta; Heart Diseases; Loeys-Dietz Syndrome; Aortic Aneurysm, Thoracic; Marfan Syndrome; Turner Syndrome; Aortic Aneurysm, Giant Congenital; Shprintzen Golberg craniosynostosis; Cutis Laxa, Autosomal Recessive, Type I; Congenital contractural arachnodactyly; Arterial Tortuosity Syndrome; Aortic Aneurysm, Familial Thoracic 1
• Other Study ID Numbers: 2000041429; 1509977311 (Other Identifier: Indiana University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No