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) 是神经发育障碍最常见的可预防原因 残疾，美国的患病率估计为 3-10/1000，地方病的患病率高达 80/1000 社区。越来越多针对产前酒精暴露的干预措施的前景 (PAE) 相关的神经行为缺陷受到临床实践中诊断困难的限制。目前已知 暴露的生物标志物对于神经行为缺陷既不敏感也不特异，部分原因是并非所有 接触过的儿童会受到影响。因此，迫切需要生物标志物来识别效果 受影响的儿童将受益于早期、量身定制的治疗干预措施。不断成长的身体 文献表明，酒精诱导的表观遗传编程改变是一种重要的潜力 FASD 中的机制，表明这种改变可以作为效应的生物标志物。印记基因 包含对产前损伤敏感的表观遗传调控基因的独特子集。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有相当大的重叠 印记基因失调的动物模型，包括学习、记忆和依恋。在产前—— 我们招募了前瞻性纵向队列，最近发现 PAE 与 93 个表达的印记基因中 11 个的胎盘表达水平。其中五个的表达变化 基因统计介导酒精对产后生长的影响，将这些改变识别为生物标志物 胎儿酒精生长受限。鉴于受影响的神经行为领域之间存在显着的重叠 在 FASD 中以及在动物模型中受印迹基因表达改变影响的患者中，酒精诱导 胎盘印记基因表达的改变也可能为 FASD 神经认知提供生物标志物 赤字。尽管大多数表观遗传标记特定于组织类型和暴露时间，但基因组印记 地图和我们的试点数据表明，在胎盘组织中发现的印记基因失调标记可能 在老年人的血液样本中可以检测到。本研究的目的是： (1) 描述 胎盘和 6 岁时获得的血液样本中与胎儿酒精相关的印记组特征； (2) 至 识别印记基因表达水平和 ICR 甲基化的变化，可以作为 效应生物标志物； (3) 验证第二个独立的血液样本中目标 1 和 2 的发现 队列。这项研究的数据将来自从开普敦招募的两个前瞻性纵向队列 南非开普敦的有色人种社区是 FASD 患病率最高的地区之一 世界。这项研究的结果将有助于确定哪些受影响的儿童将从中受益 早期治疗干预措施，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.