Stability of epigenetic structures in ART children

描述（由申请人提供）：全世界约有十分之一的夫妇患有非自愿不孕症。这部分人口转化为大量的个人谁是辅助生殖技术（ART）的潜在候选人。事实上，超过100万名儿童因体外受精（IVF）或卵胞浆内单精子注射（ICSI）而出生，通过这些程序受孕的儿童占几个西方国家所有出生人数的1%以上。尽管有许多关于ART安全性的令人放心的报告，但最近有少数报告表明，ART儿童可能会增加与基因组印记缺陷相关的罕见先天性畸形综合征的风险。至少有三名ICSI受孕的儿童被诊断患有Angelman综合征，至少有28名ART儿童（IVF和ICSI病例）被诊断患有Beckwith-Wiedemann综合征。ART儿童可能会适度增加与印记缺陷相关的罕见先天性疾病的风险，这一建议在两个方面令人不安。首先是这些特殊综合征对受影响儿童及其家庭的明显和直接影响。第二，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所能评估的更为广泛。例如，两个实验室独立报道了散发性结肠癌与胰岛素样生长因子2基因印记的组成性缺失之间的强相关性。这项研究的目的是确定ART是否增加了印记基因表达失调的可能性和/或使表观遗传染色体标记不稳定。将对通过ART受孕的500名新生儿和以传统方式受孕的500名新生儿的对照人群进行表观遗传染色体标记（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和女性X染色体失活率）的七项测量。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中表观遗传结构的不稳定。

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.