Stability of epigenetic structures in ART children

描述(申请人提供)：全球约十分之一的夫妇受到非自愿不孕症的影响。这部分人口意味着有大量个人可能成为辅助生殖技术(ART)的候选对象。事实上，已有100多万名儿童通过体外受精(IVF)或卵胞浆内单精子注射(ICSI)出生，在几个西方国家，通过这些程序怀孕的儿童占出生总数的1%以上。尽管有许多关于抗逆转录病毒治疗安全性的令人欣慰的报告，但最近有少量报告表明，抗逆转录病毒治疗儿童患罕见的先天性畸形综合征的风险可能会增加，这些综合征与基因组印记缺陷有关。至少有3名ICSI受孕的儿童被诊断出患有Angelman综合征，至少28名ART儿童(包括试管婴儿和ICSI病例)被诊断为Beckwith-Wiedemann综合征。ART儿童患与印记缺陷相关的罕见先天性疾病的风险可能略有增加，这一说法在两个方面令人担忧。首先是这些特殊症状对受影响儿童及其家庭的明显和直接影响。第二个也是更令人不安的考虑是，这些数据可能预示着ART对建立或维持基因组印记或其他表观遗传标记的影响比通过筛查罕见的先天性异常来评估的效果更广泛。例如，两个实验室已经独立报道了散发性结肠癌与胰岛素样生长因子2基因印记缺失之间的强烈关联。这项拟议的研究的目的是确定ART是否增加了印记基因表达解除调控的可能性和/或破坏了表观遗传染色体标记的稳定性。表观遗传染色体标记的七个指标(三个差异甲基化区域的DNA甲基化，三个印记基因的等位基因转录，以及女性的X染色体失活比率)将在500名通过ART受孕的新生儿和500名以传统方式受孕的对照新生儿上进行分析。将比较两个群体之间异常表观遗传标记的发生率，以确定ART程序的任何方面是否导致早期人类胚胎基因组的表观遗传结构不稳定。

DESCRIPTION (provided by applicant): Involuntary infertility affects approximately one in ten couples, worldwide. This fraction of the population translates to a large number of individuals who are potential candidates for assisted reproductive technology (ART). In fact, more than a million children have been born as the result of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and children conceived by these procedures account for more than 1% of all births in several western countries. Despite the many reassuring reports on the safety of ART, there have been a small number of recent reports suggesting that ART children may be at increased risk for rare congenital malformation syndromes that are related to defects in genome imprinting. At least three children conceived by ICSI have been diagnosed with Angelman syndrome and at least 28 ART children (both IVF and ICSI cases) have been diagnosed with Beckwith-Wiedemann syndrome. The suggestion that ART children may be at modestly increased risk for rare, congenital disorders associated with defects in imprinting is troubling on two counts. The first is the obvious and direct impact of these particular syndromes on affected children and their families. The second, and more troubling, consideration is that these data may portend more widespread effects of ART on the establishment or maintenance of genome imprints, or other epigenetic marks, than can be assessed by screening for rare congenital abnormalities. For example, a strong association between sporadic colon cancer and constitutional loss of imprinting at the insulin-like growth factor 2 gene has been reported independently by two laboratories. The purpose of the proposed study is to determine whether ART increases the possibility of deregulated expression of imprinted genes and/or destabilizes epigenetic chromosomal marking. Seven measures of epigenetic chromosomal marking (DNA methylation at three differentially methylated regions, transcription of alleles at three imprinted genes, and X-chromosome inactivation ratios in females) will be analyzed on a population of 500 newborns conceived through ART and a control population of 500 newborns conceived in the traditional fashion. The incidence of abnormal epigenetic marks will be compared between the two populations to determine whether any aspect of the ART procedure results in destabilization of epigenetic structures in the genomes of early human embryos.