PDF(Pubmed)
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 (n = 12), TS TAV (n = 13), and non-syndromic BAV (n = 6). When comparing TS with BAV to TS with no heart defects we identified a differentially methylated region encompassing the BAV-associated gene MYRF, 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 NOTCH1 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.
摘要：
特纳综合征（TS）是一种罕见的细胞遗传学疾病，由第二性染色体的完全丢失或结构变异引起。TS早期死亡的最常见原因是左侧先天性心脏病的高发生率。包括二叶主动脉瓣（BAV），这发生在大约30%的TS个体中。BAV也是普通人群中最常见的先天性心脏病，患病率为0.5-2％，男性患BAV的可能性是女性的三倍。与核型正常男性和女性相比，TS与全基因组低甲基化相关。原发性主动脉组织中DNA甲基化的改变与整倍体个体中的BAV相关。在这里，我们通过比较TSBAV（n=12）在外周血中发现的TS中与BAV相关的DNA甲基化模式存在显着差异，TSTAV（n=13），和非综合征性BAV（n=6）。当比较TS与BAV与没有心脏缺陷的TS时，我们发现了一个包含BAV相关基因MYRF的差异甲基化区域，和富集两个已知的BAV转录因子贡献者的结合位点。当比较TS与BAV与具有BAV的整倍体女性时，我们发现ChIP-seq转录因子靶标包括NOTCH1通路中的基因显著重叠富集，已知参与非综合征性BAV的病因，和其他基因是心脏瓣膜发育的重要调节因子。总的来说,这些研究结果表明,影响主动脉瓣关键发育基因的DNA甲基化改变导致TS中BAV的风险大大增加.
