Pathogenetic Basis of Aortopathy and Aortic Valve Disease
Pathogenetic Basis of Aortopathy and Aortic Valve Disease
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.
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.
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)