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.

项目摘要/摘要死产，胎儿死亡至少20周的妊娠是最常见的不良怀孕之一结果，每年影响超过300万妊娠。死胎导致了实质性的经济和受影响家庭和医疗系统的情绪燃烧。经历死产的妇女在随后怀孕的复发风险增加和其他产科并发症。虽然一个病因可能在一些夫妻中发现，在约50％的病例中，死胎是出乎意料的。可悲的是，情绪化关于无法解释的死胎的宽大遗憾，家庭的磨难加剧了，例如是罕见的事件，以及增加自我塑造和内gui的感觉。除了不频繁的非整倍性外，意外病例的基本因果遗传因素在很大程度上未知。最近，我们表明家庭中的死产骨料表明，研究了高风险中的基因家族死产的血统书将揭示对致病性遗传基因的重要见解。另外，从孕产妇的外显子组测序（WES），我们确定了小遗传异常以前无法确定。但是，我们的WES分析的结果对影响调节元素或大型多样性的致病变异的解释和鉴定基因。全基因组测序（WGS）分析来自父母，死产和活产的DNA，提供了全面检测一组遗传异常集的机会（例如，单一遗传异常核苷酸多态性，插入/缺失和结构变体，包括其余的基因组具有生化活性）。在使用父母的DNA的试点WGS研究中，无法解释的复发性胎儿死亡包括死产和活产，我们证明了继承和新发生的，即从头变体可能与胎儿死亡有关。通过较大的WGS研究和新颖的分类中共享风险变异分析，我们可以将遗传和从头变体确定为死产的因果和促成因素。调查结果将领导改善新型病理生理途径和治疗靶标的风险分层和发现。因此，我们提出以下特定目的：目标1）确定与家庭相关的新颖遗传变体和反复死胎，目标2）确定从头开始的变种，这些变体是“ intolerome”的一部分，并且与零星的死产。我们将使用父母及其后代的DNA进行WGS分析（死产和活产）。这项研究的科学目的由拟议的团队完成和增强在生殖医学和死产遗传研究领域的总体承诺和专业知识作为现有IRB批准的数据和样本。我们的研究将通过提供死胎的解释，支持丧亲和情感封闭，并促进发现生物标志物进行风险分层。