Uncovering the Etiologies of Non-immune Hydrops Fetalis

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, surveillance and in utero available treatments such as intrauterine transfusions are implemented, and postnatal treatments are promptly initiated to optimize outcomes. The overarching hypothesis is that discovering the precise etiologies of NIHF will create critical opportunities to improve outcomes through earlier, targeted pre- and postnatal care. Several important steps remain in order to uncover the genetic etiologies for cases remaining unsolved and improve care for these pregnancies. The study team proposes 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. The team 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 phenotype, and c) expand the phenotypes of all genetic in utero in utero diseases the investigators identify to optimize prenatal diagnosis and yield of genomic testing during pregnancy. 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 it is expected that this work will significantly improve the ability to understand and reshape the perinatal care for NIHF. This work will lay the foundation for redefining the approach to prenatal diagnosis, management, in utero and postnatal care for NIHF, and will create future opportunities to develop novel diagnostic algorithms and approaches to manage the complications of specific diseases underlying in utero NIHF.

The etiology of non-immune hydrops fetalis (NIHF) remains unknown in at least half of all cases after standard prenatal testing; the comprehensive approach with genomic testing and detailed phenotyping is critical for better understanding this highly morbid condition and ultimately improving outcomes. NIHF occurs in up to 1 in 1700 pregnancies and is diagnosed when abnormal fetal fluid collections (such as pericardial effusion, pleural effusion, ascites, and skin edema) are detected on prenatal ultrasound. Risks include preterm birth in 57-80% of cases, stillbirth in 17-30%, and neonatal death in 29-50%. When the etiology is unknown, critical pre- and postnatal opportunities for focused care and prompt initiation of available treatments are missed. In contrast, when an etiology such as a hereditary anemia or lysosomal storage disorder is found, prenatal 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. Many genetic etiologies may underlie NIHF, particularly single gene disorders missed by standard microarray and karyotype. Exome sequencing (ES), whole genome sequencing (WGS), and functional studies are emerging tools for prenatal diagnosis. ES examines \>20,000 genes, WGS examines these genes as well as other structural genomic changes, and functional studies such as RNA sequencing evaluate downstream effects of genomic changes. Prior to this work, these approaches had not been used to study NIHF. In a preliminary study of 127 NIHF cases unexplained by standard genetic testing, the study team identified diagnostic variants in 29% with ES and a variant of potential significance in another 9%. This yield is much higher than the 8.5-10% reported for all fetal anomalies with ES, highlighting the burden of single gene disorders in NIHF. The study team identified genetic diseases with greatly variable ultimate severity as well as pre- and postnatal management. However, important steps remain to improve care for these cases: identify additional underlying genetic variants, structural rearrangements, and candidate genes to more fully understand the genetic etiologies of NIHF; enroll a larger, racially diverse cohort to decrease disparities in disease identification; and comprehensively describe in utero and postnatal features of genetic diseases manifesting with NIHF to expand knowledge of their perinatal phenotypes and optimize the yield of prenatal sequencing. The overarching hypothesis is that discovering the precise etiologies of NIHF will create critical opportunities to improve outcomes through earlier, targeted pre- and postnatal care. The HyDROPS study (Hydrops: Diagnosing and Re-defining Outcomes with Precision Study) where 127 cases were sequenced was conducted by the PI, and the expert multidisciplinary team is ideally positioned to carry the ne trial.show_full_description

Inclusion Criteria: * Pregnant individuals whose fetus has been diagnosed with NIHF and standard prenatal testing with karyotype and/or microarray is non-diagnostic * Neonates who received a prenatal diagnosis of NIHF, but genetic testing was unable to be completed or was deferred until after delivery * Biological parents of the fetus or neonate with NIHF will be enrolled; there are no further inclusion or exclusion criteria for biological parents Exclusion Criteria: • Fetuses/neonates with prenatal presentation of * hydrops secondary to twin-twin transfusion syndrome, * a clear viral etiology, or * alloimmunization.