Abstract

Turner Syndrome (TS) is a rare cytogenetic disorder caused by the complete loss or structural variation of the second sex chromosome. The most common cause of early mortality in TS results from a high incidence of left-sided congenital heart defects, including bicuspid aortic valve (BAV), which occurs in about 30% of individuals with TS. BAV is also the most common congenital heart defect in the general population with a prevalence of 0.5-2%, with males being three-times more likely to have a BAV than females. TS is associated with genome-wide hypomethylation when compared to karyotypically normal males and females. Alterations in DNA methylation in primary aortic tissue are associated with BAV in euploid individuals. Here we show significant differences in DNA methylation patterns associated with BAV in TS found in peripheral blood by comparing TS BAV (<i>n</i> = 12), TS TAV (<i>n</i> = 13), and non-syndromic BAV (<i>n</i> = 6). When comparing TS with BAV to TS with no heart defects we identified a differentially methylated region encompassing the BAV-associated gene <i>MYRF</i>, and enrichment for binding sites of two known transcription factor contributors to BAV. When comparing TS with BAV to euploid women with BAV, we found significant overlapping enrichment for ChIP-seq transcription factor targets including genes in the <i>NOTCH1</i> pathway, known for involvement in the etiology of non-syndromic BAV, and other genes that are essential regulators of heart valve development. Overall, these findings suggest that altered DNA methylation affecting key aortic valve development genes contributes to the greatly increased risk for BAV in TS.