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Whole Exome Sequencing and Whole Genome Sequencing for Nonimmune 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.
 
ClinicalTrials.gov Identifier: NCT03911531
Recruitment Status : Recruiting
First Posted : April 11, 2019
Last Update Posted : October 25, 2022
Sponsor:
Information provided by (Responsible Party):
Huda Al-Kouatly, Thomas Jefferson University

Study Description
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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.

Condition or disease Intervention/treatment
Nonimmune Fetal Hydrops Nonimmune Hydrops in Neonate Genetic Disorders Diagnostic Test: Whole Exome Sequencing Diagnostic Test: Whole Genome Sequencing

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 Design
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Study Type : Observational
Estimated Enrollment : 55 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Whole Exome Sequencing and Whole Genome Sequencing for Nonimmune Fetal/Neonatal Hydrops
Actual Study Start Date : January 15, 2019
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Edema

Groups and Cohorts
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Group/Cohort Intervention/treatment
Fetuses
DNA obtained from amniotic fluid samples
 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.
Neonates
DNA obtained from neonatal blood samples
 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.


Outcome Measures
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Primary Outcome Measures :
  1. 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) [ Time Frame: 5 years ]
  2. Identify novel genetic disorders associated with nonimmune hydrops [ Time Frame: 5 years ]

Secondary Outcome Measures :
  1. Evaluate the incremental value of whole genome sequencing (WGS) in the evaluation of fetal hydrops when WES is negative [ Time Frame: 5 years ]
  2. Better counsel the parents about the etiology of hydrops especially if they desire a subsequent pregnancy [ Time Frame: 5 years ]

Biospecimen Retention:   Samples With DNA
DNA from amniotic fluid samples and blood samples

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients will be recruited from MFM physicians, paediatricians,and neonatologists.
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 16 years of age
  8. Hydrops was diagnosed concomitantly with intrauterine fetal demise
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03911531


Contacts
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Contact: Huda B Al-Kouatly, MD 215-955-9200 Huda.Al-kouatly@jefferson.edu
Contact: Stephanie M Rice, MS stephanie.rice@jefferson.edu

Locations
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United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Thomas Jefferson University
Investigators
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Principal Investigator: Huda B Al-Kouatly, MD Thomas Jefferson University
More Information
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
Publications:
Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, Thiruvahindrapuram B, Merico D, Jobling R, Nalpathamkalam T, Pellecchia G, Sung WWL, Wang Z, Bikangaga P, Boelman C, Carter MT, Cordeiro D, Cytrynbaum C, Dell SD, Dhir P, Dowling JJ, Heon E, Hewson S, Hiraki L, Inbar-Feigenberg M, Klatt R, Kronick J, Laxer RM, Licht C, MacDonald H, Mercimek-Andrews S, Mendoza-Londono R, Piscione T, Schneider R, Schulze A, Silverman E, Siriwardena K, Snead OC, Sondheimer N, Sutherland J, Vincent A, Wasserman JD, Weksberg R, Shuman C, Carew C, Szego MJ, Hayeems RZ, Basran R, Stavropoulos DJ, Ray PN, Bowdin S, Meyn MS, Cohn RD, Scherer SW, Marshall CR. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2018 Apr;20(4):435-443. doi: 10.1038/gim.2017.119. Epub 2017 Aug 3.
Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Nemeth AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sorensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015 Jul;47(7):717-726. doi: 10.1038/ng.3304. Epub 2015 May 18.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Huda Al-Kouatly, Assistant Professor of Obstetrics and Gynecology, Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT03911531    
Other Study ID Numbers: IRB18D.728
First Posted: April 11, 2019    Key Record Dates
Last Update Posted: October 25, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Huda Al-Kouatly, Thomas Jefferson University:
hydrops
prenatal diagnosis
amniocentesis
whole genome sequencing
Additional relevant MeSH terms:
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Hydrops Fetalis
Genetic Diseases, Inborn
Edema
Erythroblastosis, Fetal
Fetal Diseases
Pregnancy Complications
Female Urogenital Diseases and Pregnancy Complications
 Urogenital Diseases
Hematologic Diseases
alpha-Thalassemia
Thalassemia
Hemoglobinopathies
Immune System Diseases