# Epigenetic Contributions to Bicuspid Valve Aortopathy in Turner Syndrome

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $115,500

## Abstract

Turner syndrome (TS), which is caused by the complete or partial loss of the second sex chromosome, is the
most commonly occurring sex chromosome aneuploidy. Individuals with TS are phenotypically female as they
retain one complete copy of the X chromosome. This condition results in a greatly increased susceptibility for
common diseases that have a significant sex bias. Indeed the poor health trajectory in TS resulting in early
death from cardiovascular-related diseases is unprecedented. In particular, individuals with TS are ~100-times
more likely than a euploid woman to be born with a bicuspid aortic valve (BAV). BAV is the most commonly
occurring congenital heart defect in humans, and is most often seen in males in the euploid population. Having
a BAV predisposes affected individuals to adult valve disease, including calcification, valve thickening and
stenosis. Aortic regurgitation can occur promoting an increased risk for infective endocarditis. Thoracic aortic
aneurysms occur in nearly 50% of people with BAV, which can result in aortic dissection and death. The
relationship between having a congenital heart defect, BAV, and later onset aortic disease (known as bicuspid
aortic valve disease or BAVD) is not well understood. There is evidence that altered hemodynamic flow plays a
role in aneurysm progression, but it is clear that individuals with BAVD have an aneurysm susceptible aorta for
unknown reasons. Despite the seriousness of this disease, few advances have been made in understanding
the etiology. Searches for genetic variants that underlie the cause of BAVD have been of low yield indicating
that there is genetic heterogeneity or that other mechanisms are in play. One possibility is that differences in
epigenetic regulation of genes involved in aortic valve formation, and aortic wall development and homeostasis
may be risk factors. It is known that the epigenetic landscape in TS differs significantly between TS and euploid
individuals, and that there is differential gene expression in TS. In this pilot project we propose to explore
individual differences in epigenetic regulation of gene expression using TS as a phenotypically extreme model
of BAVD risk. Our preliminary data shows differential methylation of genes in the NOTCH1 pathway between
TS individuals with BAVD (cases) and those with no BAVD (controls). This is significant as mutations in
NOTCH1 are known to cause non-syndromic familial BAVD. In this study we will use DNA methyl-capture
sequencing to identify differences in gene methylation patterns in a larger TS cohort to confirm this finding (aim
1). In aim 2 we will explore the utility of using iPS cell-derived vascular smooth muscle cell lines as a model
system for differential epigenetic regulation of genes associated with BAVD. We have unique access to the TS
cohort through the NHLBI GenTAC repository in BioLINCC to support this study. This project is directly
responsive to the NHLBI Strategic Vision, particularly with rega...

## Key facts

- **NIH application ID:** 9978913
- **Project number:** 5R21HL148093-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** CHERYL L MASLEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $115,500
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978913

## Citation

> US National Institutes of Health, RePORTER application 9978913, Epigenetic Contributions to Bicuspid Valve Aortopathy in Turner Syndrome (5R21HL148093-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9978913. Licensed CC0.

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