Inherited and de novo genetic variants relevant to familial, recurrent and sporadic stillbirth

项目摘要/摘要 死产，发生在妊娠至少20周的胎儿死亡，是最常见的不良妊娠之一。 结果，全世界每年有300多万例怀孕受到影响。死产导致大量的经济和 这给受影响的家庭和医疗保健系统带来了情感负担。经历死产的妇女在 在以后的怀孕中增加其复发和其他产科并发症的风险。虽然一个 一些夫妇可能会发现病因，约50%的死产病例无法解释。可悲的是，情绪化 人们普遍对不明原因死产的误解加剧了家庭的痛苦，比如 这是一种罕见的情况，并增加了自责和内疚的感觉。除了罕见的非整倍体外， 未解释病例的潜在原因遗传因素在很大程度上是未知的。 最近，我们发现死产在家族中聚集，这表明在高危人群中研究基因 家族性死产家系将揭示致病遗传基因的重要见解。此外，整体而言- 母-子二联体的外显子组测序(WES)，我们发现了一些小的遗传异常 以前无法确定。然而，我们WES分析的结果对以下方面提出了许多挑战 解释和鉴定影响调控元件或大而多样集合的致病变异体 基因。对双亲、死产和活产的DNA进行全基因组测序分析， 提供了全面检测一整套基因异常的机会(例如，单一的 核苷酸多态、插入/缺失和结构变异，包括基因组的其余部分 具有生物化学活性)。在WGS使用父母DNA进行的一项试点研究中，原因不明的复发性胎儿死亡 包括死产和活产，我们表明遗传的和新出现的，即从头开始的变种可能 与胎儿死亡有关。通过更大的WGS研究和新的家系共享风险变异分析，我们 可以确定遗传的和从头产生的变异是死产的原因和促成因素。这些发现将导致 改进风险分层，发现新的病理生理途径和治疗靶点。 因此，我们提出了以下具体目标：目的1)识别与家族性相关的新的遗传变异 和复发性死产，目的2)找出新的变种，这些变种是“不耐受组”的一部分，与 零星死产。我们将使用父母及其后代(死产)的DNA进行WGS分析 和活产)。这项研究的科学目标得到了拟议团队的补充和加强 在生殖医学和死产遗传研究领域的总体承诺和专门知识 作为IRB批准的现有数据和样本。我们的研究将产生重大影响，通过提供 解释死产，促进丧亲和情感的结束，并推进对 风险分层的生物标志物。

PROJECT SUMMARY/ABSTRACT Stillbirth, fetal death occurring at least 20 weeks’ gestation, is one of the most common adverse pregnancy outcomes, affecting over 3 million pregnancies per year worldwide. Stillbirth leads to substantial economic and emotional burden on affected families and the health care system. Women experiencing stillbirth are at increased risk of its recurrence and other obstetric complications in subsequent pregnancies. Though an etiology may be found in some couples, stillbirth is unexplained in about 50% of cases. Sadly, emotional ordeals for families are exacerbated by widespread misconceptions about unexplained stillbirths, such as it being a rare occurrence, and by increased feelings of self-blame and guilt. Apart from infrequent aneuploidies, underlying causal genetic factors of unexplained cases are largely unknown. Recently, we showed that stillbirth aggregates in families, suggesting that investigating genes in high-risk familial stillbirth pedigrees will reveal important insights into pathogenic heritable genes. Additionally, by whole- exome sequencing (WES) of maternal-offspring dyads, we identified small genetic abnormalities that were previously impossible to ascertain.However, the results from our WES analysis pose many challenges for interpretation and identification of pathogenic variants affecting regulatory elements or a large and diverse set of genes. Whole genome sequencing (WGS) analysis of DNA from both parents, stillbirths, and live births, offers the opportunity to comprehensively detect a complete set of genetic abnormalities (e.g., single- nucleotide polymorphisms, insertion/deletions, and structural variants, including the rest of the genome that are biochemically active). In a pilot WGS study using DNA from parents, unexplained recurrent fetal death including stillbirths, and live births, we showed that inherited and newly occurring, i.e., de novo variants may be relevant to fetal death. With a larger WGS study and novel shared risk variants analyses in pedigrees, we can identify inherited and de novo variants as causal and contributory factors for stillbirth. The findings will lead to improved risk stratification and discovery of novel pathophysiologic pathways and therapeutic targets. Therefore, we propose the following Specific Aims: Aim 1) Identify novel inherited variants relevant to familial and recurrent stillbirth, Aim 2) Identify de novo variants that are part of the ‘intolerome’ and relevant to sporadic stillbirth. We will conduct WGS analysis using DNA from both parents and their offspring (stillbirths and live births). The scientific aims of this study are complemented and enhanced by the proposed team’s overall commitment and expertise in the field of reproductive medicine and in stillbirth genetic research as well as existing IRB-approved data and samples. Our study will have a significant impact by providing an explanation for stillbirth, facilitating bereavement and emotional closure, and advancing the discovery of biomarkers for risk-stratification.