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

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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.