Identification of fetal alcohol-affected children: Alterations in imprinted gene expression and methylation as biomarkers of neurobehavioral and growth impairment.

摘要 胎儿酒精谱系障碍（FASD）是神经发育障碍中最常见的可预防的原因。 残疾，在美国的患病率估计为3-10/1000，在地方病中高达80/1000 社区.越来越多针对产前酒精暴露的干预措施的承诺 （PAE）相关的神经行为缺陷在临床实践中受到诊断困难的限制。目前已知 暴露的生物标志物对神经行为缺陷既不敏感也不特异，部分原因是并非所有的 受影响的儿童。因此，迫切需要有效的生物标志物来识别 受影响的儿童将受益于早期，量身定制的治疗干预措施。越来越多的 文献表明，酒精诱导的表观遗传编程的改变是一个重要的潜力， FASD的机制，这表明这种改变可能作为生物标志物的效果。印记基因 包括对产前损伤敏感的表观遗传学调节基因的独特子集。有 受FASD影响的神经行为领域与实验中观察到的神经行为领域之间存在相当大的重叠， 印迹基因失调的动物模型，包括学习、记忆和依恋。在产前- 招募，前瞻性纵向队列，我们最近发现，PAE与改变， 胎盘表达水平的93个表达印迹基因中的11个。其中五个的表达变化 基因统计学上介导的酒精对出生后生长的影响，确定这些变化作为生物标志物 胎儿酒精生长受限考虑到受影响的神经行为领域之间的显著重叠 在FASD和动物模型中受印记基因表达改变影响的患者中，酒精诱导的 胎盘印迹基因表达的改变也可能为FASD神经认知障碍提供生物标志物。 赤字虽然大多数表观遗传标记是特定于组织类型和暴露时间， 图谱和我们的试验数据表明，在胎盘组织中发现的印记基因失调的标记物可能 在老年人的血液样本中检测到。本研究的目的是：（1）表征 在胎盘和6岁时获得的血液样本中的胎儿酒精相关印记组签名;（2） 鉴定印迹基因表达水平和ICR甲基化的改变， （3）在来自第二个独立研究的血液样本中验证目的1和2中的结果。 队列。本研究的数据将来自两个前瞻性纵向队列， 南非开普敦的有色人种社区，那里的FASD患病率是世界上最高的。 世界这项研究的结果将有可能确定受影响的儿童谁将受益于 早期治疗干预，但目前的诊断工具可能无法检测到。

Abstract Fetal alcohol spectrum disorders (FASD) are the most common preventable cause of neurodevelopmental disabilities, with prevalence estimates of 3-10/1000 individuals in the US and up to 80/1000 in endemic communities. The promise of an increasing number of interventions tailored to prenatal alcohol exposure (PAE)-related neurobehavioral deficits is limited by diagnostic difficulties in clinical practice. Currently known biomarkers of exposure are neither sensitive nor specific for neurobehavioral deficits, in part because not all exposed children are affected. There is, therefore, a critical need for biomarkers of effect to identify affected children who would benefit from early, tailored therapeutic interventions. A growing body of literature has demonstrated alcohol-induced alterations in epigenetic programming as an important potential mechanism in FASD, suggesting that such alterations may serve as biomarkers of effect. Imprinted genes comprise a unique subset of epigenetically regulated genes that is sensitive to prenatal insults. There is considerable overlap between the neurobehavioral domains affected by FASD and those seen in experimental animal models of imprinted gene dysregulation, including learning, memory, and attachment. In a prenatally- recruited, prospective longitudinal cohort, we recently found that PAE was associated with alterations in placental level of expression of 11 of 93 expressed imprinted genes. Expression changes for five of these genes statistically mediated effects of alcohol on postnatal growth, identifying these alterations as biomarkers of fetal alcohol growth restriction. Given the remarkable overlap between the neurobehavioral domains affected in FASD and those affected by alteration of imprinted gene expression in animal models, alcohol-induced alterations in placental imprinted gene expression may also provide biomarkers for FASD neurocognitive deficits. Although most epigenetic marks are specific to tissue-type and timing of exposure, genomic imprinting maps and our pilot data indicate that markers of imprinted gene dysregulation identified in placental tissue may be detected in blood samples obtained at older ages. The aims of this study are: (1) To characterize the fetal alcohol-related imprintome signature in the placenta and in blood samples obtained at 6 yr; (2) To identify alterations in imprinted gene level of expression and ICR methylation that can serve as biomarkers of effect; (3) To validate findings in Aims 1 and 2 in blood samples from a 2nd, independent cohort. The data for this study will come from two prospective longitudinal cohorts recruited from the Cape Coloured community in Cape Town, South Africa, where the prevalence of FASD is among the highest in the world. Results from this study will make it possible to identify affected children who would benefit from early therapeutic interventions but would likely not be detected by current diagnostic tools.