Bicuspid Aortic Valves (BAV) can cause premature deaths due to aortic stenosis, aortic regurgitation or Thoracic Aortic Aneurysms leading to acute aortic Dissections (TAAD). The genetic causes of BAV remain largely unknown due to the substantial genetic and clinical heterogeneity of complications related to BAV. We determined that rare Copy Number Variants (CNVs) are significantly enriched in BAV patients who experienced early onset clinical complications. The overall goal of my research is to identify causal genetic variants that are responsible for both the BAV and its complications, and to establish the clinical phenotypes that are associated with each new gene.
The specific aims of my proposal are: 1) to characterize a cohort of BAV patients with severe and early onset complications, 2) to identify rare CNVs that are associated with severe BAV-related complications and 3) to identify rare exome sequence variants in patients with severe phenotypes or distinctive clinical features who have available parents or affected relatives. Our discoveries could provide new insights into the etiology of BAV disease and may also be useful for risk stratification or clinical decision-making about surveillance and elective interventions for BAV patients.

Public Health Relevance

Bicuspid Aortic Valve (BAV) is the most common congenital heart defect. BAV affects 1% of the adult population, but is responsible up to 50% of aortic valve replacements and 10% of fatal acute aortic dissections. The goal of the proposed research is to reduce the morbidity and mortality related to BAV by identifying individuals who are genetically predisposed to early onset complications and may benefit from intensified screening, medical therapies or prophylactic surgical interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL137028-01
Application #
9290031
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Evans, Frank
Project Start
2017-05-05
Project End
2021-03-31
Budget Start
2017-05-05
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$385,000
Indirect Cost
$135,000
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Prakash, Siddharth K; Milewicz, Dianna M (2018) X Marks the Spot: The Profound Impact of Sex on Aortic Disease. Arterioscler Thromb Vasc Biol 38:9-11
Alhafez, Bader Aldeen; Truong, Van Thi Thanh; Ocazionez, Daniel et al. (2018) Aortic arch tortuosity, a novel biomarker for thoracic aortic disease, is increased in adults with bicuspid aortic valve. Int J Cardiol :