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

NCT03911531 | Recruiting

• 1 other identifier: IRB18D.728
• Study Type: observational
• Target: 55
• Locations: 1 country
• Sites: 1

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.

Conditions

Nonimmune Fetal Hydrops; Nonimmune Hydrops in Neonate; Genetic Disorders

Keywords

hydrops; prenatal diagnosis; amniocentesis; whole genome sequencing

Outcome Measures

Primary Outcomes (2)

• 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

• Identify novel genetic disorders associated with nonimmune hydrops

  5 years

Secondary Outcomes (2)

• Evaluate the incremental value of whole genome sequencing (WGS) in the evaluation of fetal hydrops when WES is negative

  5 years

• Better counsel the parents about the etiology of hydrops especially if they desire a subsequent pregnancy

  5 years

Study Arms (2)

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

Interventions

Whole Exome Sequencing DIAGNOSTIC_TEST

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.

Fetuses; Neonates

Whole Genome Sequencing DIAGNOSTIC_TEST

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.

Fetuses; Neonates

Eligibility Criteria

• Age: 16 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Patients will be recruited from MFM physicians, paediatricians,and neonatologists.

You may qualify if:

• Fetal hydrops identified anytime in pregnancy after the first trimester
• Parents are planning to proceed with amniocentesis as a routine workup for hydrops.
• Both parents are available for blood sample collection
• Normal CMA and normal karyotype if performed
• Negative workup for Parvovirus B19, cytomegalovirus, toxoplasmosis, and syphilis
• 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.

You may not qualify if:

• Microarray was abnormal or karyotype was abnormal
• Hydrops caused by congenital infection
• Fetomaternal hemorrhage was a documented etiology for hydrops
• Parental DNA cannot be obtained for either parents
• Donor egg or donor sperm were utilized for conception
• Fetus/Infant diagnosed with lysosomal storage disease
• Pregnant woman or father of the baby less than 16 years of age
• Hydrops was diagnosed concomitantly with intrauterine fetal demise

Sponsors & Collaborators

• Thomas Jefferson University: lead

Study Sites (1)

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

RECRUITING

Related Publications (6)

• Society for Maternal-Fetal Medicine (SMFM); Norton ME, Chauhan SP, Dashe JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. Am J Obstet Gynecol. 2015 Feb;212(2):127-39. doi: 10.1016/j.ajog.2014.12.018. Epub 2014 Dec 31.

  PMID: 25557883 BACKGROUND

• Whybra C, Mengel E, Russo A, Bahlmann F, Kampmann C, Beck M, Eich E, Mildenberger E. Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF): more common than assumed? Report of four cases with transient NIHF and a review of the literature. Orphanet J Rare Dis. 2012 Nov 8;7:86. doi: 10.1186/1750-1172-7-86.

  PMID: 23137060 BACKGROUND

• 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.

  PMID: 28771251 BACKGROUND

• 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.

  PMID: 25985138 BACKGROUND

• Rice SM, Varotsis DF, Wodoslawsky S, Critchlow E, Liu R, McLaren RA Jr, Makhamreh MM, Firman B, Berger SI, Al-Kouatly HB. Prenatal Phenotype of Alkuraya-Kucinskas Syndrome: A Novel Case and Systematic Literature Review. Prenat Diagn. 2024 Oct;44(11):1381-1397. doi: 10.1002/pd.6637. Epub 2024 Sep 3.

  PMID: 39228063 DERIVED

• Raymond M, Critchlow E, Rice SM, Wodoslawsky S, Berger SI, Hegde M, Empey PE, Al-Kouatly HB. Fetal pharmacogenomics: A promising addition to complex neonatal care. Mol Genet Metab. 2022 Sep-Oct;137(1-2):140-145. doi: 10.1016/j.ymgme.2022.08.002. Epub 2022 Aug 12.

  PMID: 36029725 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

DNA from amniotic fluid samples and blood samples

MeSH Terms

Conditions

Genetic Diseases, Inborn; Edema

Interventions

Exome

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Genome; Genetic Structures; Genetic Phenomena

Study Officials

• Huda B Al-Kouatly, MD

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Huda B Al-Kouatly, MD

CONTACT

215-955-9200; Huda.Al-kouatly@jefferson.edu

Stephanie M Rice, MS

CONTACT

stephanie.rice@jefferson.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Obstetrics and Gynecology

Study Record Dates

• First Submitted: April 9, 2019
• First Posted: April 11, 2019
• Study Start: January 15, 2019
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: September 11, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share

Locations

US (1)