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.