Stability of epigenetic structures in ART children

描述（由申请人提供）：全世界大约十分之一的夫妇患有非自愿不孕。这部分人口转化为大量潜在的辅助生殖技术（ART）候选人。事实上，通过体外受精（IVF）或卵胞浆内单精子注射（ICSI）出生的儿童已经超过100万，在一些西方国家，通过这些方法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放心的报告，但最近有少数报告表明，接受抗逆转录病毒治疗的儿童患与基因组印记缺陷有关的罕见先天性畸形综合征的风险可能增加。至少有三个通过ICSI受孕的孩子被诊断为Angelman综合征，至少有28个ART儿童（IVF和ICSI病例）被诊断为Beckwith-Wiedemann综合征。抗逆转录病毒治疗儿童患与印迹缺陷相关的罕见先天性疾病的风险可能略有增加，这一建议令人不安，原因有两点。首先是这些特殊综合症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对基因组印记或其他表观遗传标记的建立或维持的更广泛的影响，而不是通过筛查罕见的先天性异常来评估的。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基因印记的体质缺失之间的密切联系。拟议研究的目的是确定ART是否增加了印迹基因表达失控的可能性和/或破坏表观遗传染色体标记的稳定性。研究人员将对500名通过ART受孕的新生儿和500名以传统方式受孕的对照组进行7项表观遗传染色体标记（3个差异甲基化区域的DNA甲基化、3个印迹基因的等位基因转录和女性x染色体失活率）分析。将比较两个人群中异常表观遗传标记的发生率，以确定ART手术是否有任何方面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.