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

与家族性、复发性和散发性死产相关的遗传性和从头遗传变异

• 批准号: 10719376
• 负责人: Tsegaselassie Workalemahu
• 金额: $ 64.3万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719376
• 关键词: Affect; Alleles; Aneuploidy; Benchmarking; Bereavement; Biochemical; Biological; Birth; Caring; Clinical Data; Code; Complement; Couples; DNA; DNA Library; DNA analysis; Data; Data Sources; Development; Diagnosis; Economics; Emotional; Etiology; Family; Family member; Fathers; Feeling; Fetal Death; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Screening; Genome; Genomic Segment; Germ-Line Mutation; Goals; Guilt; Haplotypes; Healthcare Systems; Heritability; Heterogeneity; Human Development; Infection; Inherited; Institutional Review Boards; Karyotype; Link; Live Birth; Medical; Medical Genetics; Medical Records; Mission; Molecular; Molecular Abnormality; National Institute of Child Health and Human Development; Outcome; Parents; Pathogenicity; Pathway interactions; Perinatal mortality demographics; Perinatology; Phenotype; Pilot Projects; Population Database; Pregnancy; Prevention; Probability; Recurrence; Regulatory Element; Reproductive Medicine; Resources; Rest; Risk; Sampling; Single Nucleotide Polymorphism; Techniques; Technology; Uncertainty; Utah; Validation; Variant; Woman; adverse pregnancy outcome; base; biomarker discovery; biomarker identification; birth control; case control; causal variant; clinical phenotype; cohort; de novo mutation; exome sequencing; experience; fetal; genetic analysis; genetic disorder diagnosis; genetic pedigree; genetic variant; genome sequencing; high risk; improved; innovation; insertion/deletion mutation; insight; loss of function; new therapeutic target; novel; obstetrical complication; offspring; perinatal outcomes; population based; prevent; recruit; risk sharing; risk stratification; risk variant; segregation; stillbirth; targeted sequencing; therapeutic target; whole genome

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.

项目摘要/摘要 死产是指妊娠20周以上发生的胎儿死亡，是最常见的不良妊娠之一 每年影响全球300多万例妊娠。死产导致大量的经济和 对受影响的家庭和卫生保健系统造成情感负担。经历死产的妇女在 增加了以后怀孕时复发和其他产科并发症的风险。虽有 在某些夫妇中可能发现病因，但在约50%的病例中死胎原因不明。可悲的是，情绪化 对不明原因死产的普遍误解加剧了家庭的痛苦， 这是一种罕见的情况，并增加了自责和内疚的感觉。除了罕见的非整倍性， 无法解释的病例的潜在致病遗传因素在很大程度上是未知的。 最近，我们发现死胎聚集在家庭中，这表明研究高风险的基因 家族性死产家系将揭示致病性遗传基因的重要见解。此外，整体而言- 通过对母亲-后代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，我们的WES分析结果对 解释和鉴定影响调控元件或大量不同集合的致病性变体 基因。全基因组测序（WGS）分析来自父母双方、死胎和活产的DNA， 提供了全面检测一整套遗传异常的机会（例如，表示“单”之义 核苷酸多态性、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）。在一项使用父母DNA的WGS试点研究中， 包括死产和活产，我们表明，遗传和新发生的，即，新生变体可 与胎儿死亡有关通过更大规模的WGS研究和家系中新的共享风险变异分析，我们 可以识别遗传和新生变异作为死产的因果和促成因素。调查结果将导致 改善风险分层和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：目标1）确定与家族性疾病相关的新的遗传变异， 目的2）鉴定作为“不耐受组”的一部分并与以下相关的从头变异： 零星死胎我们将使用父母及其后代（死胎）的DNA进行WGS分析 活产）。这项研究的科学目标得到了拟议团队的补充和加强。 在生殖医学和死胎遗传研究领域的全面承诺和专业知识 现有IRB批准的数据和样本。我们的研究将通过提供一个 解释死产，促进丧亲之痛和情感关闭，并推进发现 用于风险分层的生物标志物。