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Whole Exome Sequencing and Whole Genome Sequencing for Non-immune Fetal/Neonatal Hydrops

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03911531
Recruitment Status : Recruiting
First Posted : April 11, 2019
Last Update Posted : April 12, 2019
Information provided by (Responsible Party):
Huda Al-Kouatly, Thomas Jefferson University

Tracking Information
First Submitted Date April 9, 2019
First Posted Date April 11, 2019
Last Update Posted Date April 12, 2019
Actual Study Start Date January 15, 2019
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 9, 2019)
  • Identify known single gene disorders that would not be detected by microarray as a cause of non-immune fetal hydrops by performing whole exome sequencing (WES) [ Time Frame: 3 years ]
  • Identify novel genetic disorders associated with non-immune hydrops [ Time Frame: 3 years ]
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: April 9, 2019)
  • Evaluate the incremental value of whole genome sequencing (WGS) in the evaluation of fetal hydrops when WES is negative [ Time Frame: 3 years ]
  • Better counsel the parents about the etiology of hydrops especially if they desire a subsequent pregnancy [ Time Frame: 3 years ]
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title Whole Exome Sequencing and Whole Genome Sequencing for Non-immune Fetal/Neonatal Hydrops
Official Title Whole Exome Sequencing and Whole Genome Sequencing for Non-immune Fetal/Neonatal Hydrops
Brief Summary Brief Summary: Non-immune 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 Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
DNA from amniotic fluid samples and blood samples
Sampling Method Non-Probability Sample
Study Population Patients will be recruited from MFM physicians, paediatricians,and neonatologists.
  • Non-immune Fetal Hydrops
  • Non-Immune Hydrops in Neonate
  • Genetic Disorders
  • Diagnostic Test: Whole Exome Sequencing
    Whole exome sequencing (WES) provides more detailed information through greater resolution, identifying single base-pair changes and small insertions and deletions. WES performs sequencing on the protein-coding exons, which are contained in 1-2% of the genome but make up over 85% of all known pathogenic mutations.
  • Diagnostic Test: Whole Genome Sequencing
    Whole Genome Sequencing (WGS) has emerged in recent years as a diagnostic tool that sequences the entire genome and can pick up insertions or deletion of bases, structural variants and intronic single nucleotide variations.
Study Groups/Cohorts
  • Fetuses
    DNA obtained from amniotic fluid samples
    • Diagnostic Test: Whole Exome Sequencing
    • Diagnostic Test: Whole Genome Sequencing
  • Neonates
    DNA obtained from neonatal blood samples
    • Diagnostic Test: Whole Exome Sequencing
    • Diagnostic Test: Whole Genome Sequencing
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: April 9, 2019)
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 2021
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

The following inclusion criteria will apply:

  1. Fetal hydrops identified anytime in pregnancy after the first trimester
  2. Parents are planning to proceed with amniocentesis as a routine workup for hydrops.
  3. Both parents are available for blood sample collection
  4. Normal CMA and normal karyotype if performed
  5. Negative workup for Parvovirus B19, cytomegalovirus, toxoplasmosis, and syphilis
  6. Negative fetomaternal hemorrhage workup as a cause for hydrops For cases of neonatal hydrops, the criteria for invasive prenatal testing will not be required as a postnatal blood sample from the hydropic infant will be the source of proband DNA.

The following exclusion criteria will apply:

  1. Microarray was abnormal or karyotype was abnormal
  2. Hydrops caused by congenital infection
  3. Fetomaternal hemorrhage was a documented etiology for hydrops
  4. Parental DNA cannot be obtained for either parents
  5. Donor egg or donor sperm were utilized for conception
  6. Fetus/Infant diagnosed with lysosomal storage disease
  7. Pregnant woman or father of the baby less than 18 years of age
  8. Hydrops was diagnosed concomitantly with intrauterine fetal demise
Sexes Eligible for Study: All
Ages 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers No
Contact: Huda B Al-Kouatly, MD 215-955-9200
Contact: Mona M Makhamreh, MD
Listed Location Countries United States
Removed Location Countries  
Administrative Information
NCT Number NCT03911531
Other Study ID Numbers IRB18D.728
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Yes
Responsible Party Huda Al-Kouatly, Thomas Jefferson University
Study Sponsor Thomas Jefferson University
Collaborators Not Provided
Principal Investigator: Huda B Al-Kouatly, MD Thomas Jefferson University
PRS Account Thomas Jefferson University
Verification Date April 2019