Uncovering the etiologies of non-immune hydrops fetalis through comprehensive genomic analyses and phenotyping

通过全面的基因组分析和表型分析揭示非免疫性胎儿水肿的病因

基本信息

批准号：
10570889
负责人：
Teresa N Sparks
金额：
$ 69.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570889
关键词：
Affect Algorithms Anemia Ascites Autopsy Bioinformatics Biometry Candidate Disease Gene Caring Clinical Management Collaborations Collection Computational Biology Counseling Country Data Diagnosis Diagnostic Disease Early Diagnosis Edema Enrollment Etiology Evaluation Family Fetus Foundations Future Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genomics Hydrops Fetalis Individual Inherited Intrauterine Blood Transfusion Karyotype Knowledge Liquid substance Medical Genetics Medical center Mendelian disorder Mentored Clinical Scientist Development Program Molecular Genetics Morbidity - disease rate Multicenter Studies Outcome Pathogenicity Pericardial effusion Perinatal Perinatal Care Perinatology Phenotype Pleural effusion disorder Positioning Attribute Postnatal Care Pregnancy Pregnant Women Premature Birth Prenatal Diagnosis Race Reporting Risk Sample Size Severities Shapes Skin Testing Variant Work accurate diagnosis clinically significant cohort diagnostic accuracy diagnostic algorithm disease diagnosis disparity reduction exome sequencing experience fetal genetic epidemiology genetic testing genetic variant genome sequencing improved improved outcome in utero mortality multidisciplinary neonatal death neonate novel novel diagnostics personalized approach phenotypic data postnatal prenatal prenatal testing prospective racial diversity stillbirth tool transcriptome sequencing ultrasound whole genome

项目摘要

PROJECT SUMMARY Non-immune hydrops fetalis (NIHF) is diagnosed on prenatal ultrasound when abnormal fluid collections are seen in the fetus. NIHF carries significant risks of stillbirth, preterm birth, and postnatal morbidity and mortality, particularly when the etiology remains unknown and critical opportunities for focused care and implementation of treatments are missed. In contrast, when an etiology is found, both pre- and postnatal management are directly impacted: counseling is focused, risks to the fetus and neonate are accurately anticipated, in utero surveillance and available treatments such as intrauterine transfusions are implemented, and postnatal treatments are promptly initiated to optimize outcomes. Our overarching hypothesis is that discovering the precise etiologies of NIHF will create critical opportunities to improve outcomes through earlier, targeted pre- and postnatal care. In our preliminary study of 127 NIHF cases unexplained by standard microarray or karyotype, we identified pathogenic or likely pathogenic variants implicating a genetic disease in 29% with exome sequencing (ES), as well as a variant of potential clinical significance in another 9%. Importantly, the diseases we identified are also greatly variable in their ultimate severity as well as in their pre- and postnatal clinical management. However, several important steps remain in order to uncover the genetic etiologies for cases remaining unsolved and improve our care for these pregnancies. As such, we propose a multicenter collaboration to discover additional genetic diseases and novel variants underlying NIHF in a prospectively enrolled, large and diverse cohort utilizing whole genome sequencing (WGS) and RNA sequencing. We will further perform comprehensive phenotyping to: a) collect detailed postnatal phenotypes and outcomes, b) re-analyze WGS data utilizing postnatal phenotype to identify diagnoses missed when sequencing algorithms incorporated only in utero phenotype, and c) expand the in utero phenotypes of all genetic diseases we identify to optimize prenatal diagnosis and yield of genomic testing during pregnancy. Our multidisciplinary team is ideally positioned to excel, and includes experienced individuals in Perinatology, Clinical and Molecular Genetics, Statistical Genetics, Genetic Epidemiology, Bioinformatics, Computational Biology, and Biostatistics. Such a focused and comprehensive approach to the evaluation and diagnosis of NIHF has not previously been performed, particularly in a large and diverse cohort, and we expect that this work will significantly improve our ability to understand and reshape the perinatal care for NIHF. Our work will lay the foundation for redefining the approach to prenatal diagnosis, in utero management, and postnatal care for NIHF, and will create future opportunities to develop novel diagnostic algorithms and in utero approaches to manage the complications of specific diseases underlying NIHF. Only through this precision approach can we improve the course for fetuses and families affected by NIHF.

项目概要当液体收集异常时，可通过产前超声诊断出非免疫性胎儿水肿 (NIHF) 可见于胎儿。 NIHF 具有死产、早产和产后发病的重大风险，死亡率，特别是当病因仍然未知且有关键机会进行集中护理和治疗时错过了治疗的实施。相反，当找到病因后，产前和产后管理受到直接影响：咨询重点突出，胎儿和新生儿面临的风险准确预计，实施宫内监测和宫内输血等可用治疗，并及时启动产后治疗以优化结果。我们的总体假设是发现 NIHF 的确切病因将为通过早期、有针对性的产前和产后护理。我们对 127 例无法用标准解释的 NIHF 病例进行了初步研究通过微阵列或核型，我们鉴定出与遗传病有关的致病性或可能的致病性变异 29% 进行了外显子组测序 (ES)，另外 9% 进行了具有潜在临床意义的变异。重要的是，我们发现的疾病在其最终严重程度以及发病前也存在很大差异。和产后临床管理。然而，为了揭示遗传因素，还有几个重要的步骤需要完成。尚未解决的病例的病因并改善我们对这些怀孕的护理。因此，我们建议进行多中心合作，以发现其他遗传疾病和新的遗传疾病。利用全基因组前瞻性招募的大型多样化队列中潜在的 NIHF 变异测序 (WGS) 和 RNA 测序。我们将进一步进行全面的表型分析以：a) 收集详细的产后表型和结果，b) 利用产后表型重新分析 WGS 数据以确定当测序算法仅纳入子宫表型时，诊断会被遗漏，并且 c) 扩大子宫内表型我们确定的所有遗传疾病的子宫表型，以优化产前诊断和基因组检测的产量怀孕期间。我们的多学科团队处于理想的位置，能够脱颖而出，其中包括经验丰富的围产期学、临床和分子遗传学、统计遗传学、遗传流行病学、生物信息学、计算生物学和生物统计学。这种重点突出、全面的方法以前从未对 NIHF 进行过评估和诊断，特别是在大型且多样化的队列中，我们期望这项工作将显着提高我们理解和重塑围产期护理的能力对于NIHF。我们的工作将为重新定义子宫内产前诊断方法奠定基础 NIHF 的管理和产后护理，并将为未来开发新的诊断方法创造机会管理 NIHF 特定疾病并发症的算法和子宫内方法。仅有的通过这种精确的方法，我们可以改善受 NIHF 影响的胎儿和家庭的治疗过程。