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

Thomas Jefferson University55 enrolled

Overview

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.

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

Interventions

Whole Exome SequencingDIAGNOSTIC_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.

Whole Genome SequencingDIAGNOSTIC_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.

Eligibility

Sex: ALLMin age: 16 YearsMax age: 55 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Identify novel genetic disorders associated with nonimmune hydrops

Time frame: 5 years

Secondary Outcomes

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

Time frame: 5 years

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

Time frame: 5 years

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts