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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要死产，即妊娠至少 20 周时发生的胎儿死亡，是最常见的不良妊娠之一每年影响全球超过 300 万例妊娠的死产会带来巨大的经济和经济损失。遭受死产的妇女受到影响的家庭和医疗保健系统承受着巨大的情感负担。在随后的妊娠中复发和其他产科并发症的风险增加。一些夫妇可能会发现病因，大约 50% 的死产原因不明，可悲的是，情绪激动。对不明原因死产的普遍误解加剧了家庭的磨难，例如这是一种罕见的情况，除了罕见的非整倍体之外，还会增加自责和内疚感。不明原因病例的潜在致病遗传因素在很大程度上尚不清楚。最近，我们发现死产在家庭中聚集，这表明研究高危人群的基因此外，家族死产谱系还将通过整体揭示对致病遗传基因的重要见解。通过对母子二元组的外显子组测序（WES），我们发现了小的遗传异常以前无法确定。然而，我们的 WES 分析结果对影响调控元件或大量多样化的致病变异的解释和识别对父母双方、死产和活产的 DNA 进行全基因组测序 (WGS) 分析，提供了全面检测一整套遗传异常（例如，单基因异常）的机会核苷酸多态性、插入/缺失和结构变异，包括基因组的其余部分具有生化活性）在一项使用父母 DNA 的试点全基因组测序研究中，出现了不明原因的反复胎儿死亡。包括死产和活产，我们表明遗传性和新发生的变异（即从头变异）可能通过更大规模的全基因组测序研究和谱系中新的共享风险变异分析，我们发现与胎儿死亡相关。可以将遗传变异和新发变异识别为死产的因果因素。这些发现将导致死产。改善风险分层并发现新的病理生理学途径和治疗靶点。因此，我们提出以下具体目标：目标 1) 识别与家族相关的新遗传变异和复发性死产，目标 2) 识别属于“intolerome”一部分且与以下疾病相关的新发变异：我们将使用父母及其后代的 DNA 进行全基因组测序 (WGS) 分析（死产）。和活产）。本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学研究领域的总体承诺和专业知识作为现有的 IRB 批准的数据和样本，我们的研究将通过提供一个重大影响。对死产的解释，促进丧亲和情感的终结，并促进对死产的发现用于风险分层的生物标志物。