Whole Exome Sequencing and Whole Genome Sequencing for Nonimmune Fetal/Neonatal Hydrops

Recruiting

• Conditions: Nonimmune Hydrops in Neonate; Genetic Disorders; Nonimmune Fetal Hydrops
• Interventions: Diagnostic Test: Whole Exome Sequencing; Diagnostic Test: Whole Genome Sequencing

• Registration Number: NCT03911531
• Lead Sponsor: Thomas Jefferson University

Brief Summary

Brief Summary: Nonimmune hydrops fetalis (NIHF) is a potentially fatal condition characterized by abnormal fluid accumulation in two or more fetal compartments. Numerous etiologies may lead to NIHF, and the underlying cause often remains unclear (1). The current standard of genetic diagnostic testing includes a fetal karyotype and chromosomal microarray (CMA), with an option to pursue single gene testing on amniocytes collected by amniocentesis (2). A large subgroup of the NIHF causes includes single gene disorders that are not diagnosed with the standard genetic workup for hydrops. Currently, nearly 1 in 5 cases of NIHF is defined as idiopathic, meaning there is no identified etiology (2). The investigators believe this is because the causes of NIHF are not completely investigated, specifically single gene disorders. Our research study aims to increase the diagnostic yield by performing whole exome sequencing (WES) and whole genome sequencing (WGS) on prenatal and neonatal NIHF cases when standard genetic testing is negative, identifying known and new genes, thus providing vital information to families regarding the specific diagnosis and risk to future pregnancies. The investigators plan to perform WES as the initial diagnostic test. If WES is negative, then the investigators will proceed to perform WGS.

Detailed Description

This is a prospective cohort study design for fetuses or neonates affected with NIHF. Mother-father-fetus trios of pregnancies complicated by idiopathic non-immune fetal hydrops will be identified. These patients will be counseled by a Maternal-Fetal Medicine specialist as would be the routine. As part of the routine work-up, amniocentesis will be recommended for karyotype, CMA and an infectious work-up. Amniocentesis will be performed by the Maternal-Fetal Medicine specialist of the referring institution. The patient will also be offered genetic counseling (routine). Subjects will be offered enrollment when inclusion criteria are met. After enrollment, the following samples will be collected: (1) maternal blood (2) paternal blood, (3) fetal DNA isolated from amniocytes (4) neonatal blood when referral is done postnatally. The WES results will be reported to the genetic counselor dedicated to the study. The parents will be contacted by the genetic counselor and counseled on the findings whether they were positive or negative. The result will also be communicated to the patient's primary MFM provider or pediatrician and appropriate referrals to pediatric genetics specialists will be made by the primary provider. In cases where no genetic disorder is identified, the sample will be stored and then subsequently whole genome sequencing will be performed.

Study Timeline

• Study Start: 2019-01-15
• Study First Submitted: 2019-04-09
• Study First Submitted QC: 2019-04-09
• Study First Posted: 2019-04-11
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-18
• Last Update Posted: 2024-11-21
• Primary Completion: 2025-06-30
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 55

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Neonates	Whole Exome Sequencing	DNA obtained from neonatal blood samples
Fetuses	Whole Exome Sequencing	DNA obtained from amniotic fluid samples
Fetuses	Whole Genome Sequencing	DNA obtained from amniotic fluid samples
Neonates	Whole Genome Sequencing	DNA obtained from neonatal blood samples

Primary Outcome Measures

Name	Time	Method
Identify novel genetic disorders associated with nonimmune hydrops	5 years
Identify known single gene disorders that would not be detected by microarray as a cause of nonimmune fetal hydrops by performing whole exome sequencing (WES)	5 years

Secondary Outcome Measures

Name	Time	Method
Better counsel the parents about the etiology of hydrops especially if they desire a subsequent pregnancy	5 years
Evaluate the incremental value of whole genome sequencing (WGS) in the evaluation of fetal hydrops when WES is negative	5 years

Trial Locations

Locations (1)

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States