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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：
10345918
负责人：
Teresa N Sparks
金额：
$ 77.29万
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/10345918
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 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 Reporting Risk SECTM1 gene Sample Size Severities Skin Test Result Testing Variant Work accurate diagnosis clinically significant cohort diagnostic accuracy diagnostic algorithm disease diagnosis 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.

项目总结