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

• 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
• 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

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.

项目摘要 非免疫性胎儿水肿（NIHF）是产前超声诊断时，异常液体收集 在胎儿中可见。NIHF具有死胎、早产和产后发病的显著风险， 死亡率，特别是当病因仍然未知时，以及重点护理的关键机会， 治疗的实施被遗漏。相反，当发现病因时，产前和产后 管理直接受到影响：咨询是集中的，胎儿和新生儿的风险是准确的， 预计，子宫内监测和可用的治疗，如子宫内输血的实施， 及时启动产后治疗以优化结果。我们的首要假设是 发现NIHF的确切病因将创造关键的机会， 有针对性的产前和产后护理。在我们对127例标准无法解释的NIHF病例的初步研究中 微阵列或核型分析，我们确定了致病或可能致病的变异，涉及遗传疾病， 29%与外显子组测序（ES），以及在另外9%的潜在临床意义的变体。 重要的是，我们确定的疾病在其最终严重程度以及其前期严重程度方面也存在很大差异。 和产后临床管理。然而，为了揭示基因，还有几个重要步骤 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，我们提出了一个多中心的合作，以发现其他遗传疾病和新的 使用全基因组前瞻性招募的大型多样化队列中NIHF的潜在变异 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 详细的出生后表型和结果，B）利用出生后表型重新分析WGS数据， 当测序算法仅结合子宫内表型时错过诊断，以及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 孕期我们的多学科团队是理想的定位，以出类拔萃，并包括经验丰富的 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。这种重点突出和全面的方法， NIHF的评估和诊断以前没有进行过，特别是在大的和多样化的队列中， 我们希望这项工作将大大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产前诊断的方法奠定基础， 管理和产后护理，并将创造未来的机会，开发新的诊断 算法和子宫内方法来管理NIHF基础的特定疾病的并发症。只 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进程。