Utility of Whole Genome Sequencing in Fetuses With Abnormal Ultrasound Findings

NCT07606989 | Recruiting

• 1 other identifier: IRB-20260095-R
• Study Type: observational
• Target: 1,000
• Locations: 1 country
• Sites: 4

Brief Summary

The goal of this observational study is to learn if whole-genome sequencing (WGS) can help find the genetic cause in fetuses with structural abnormalities that remain unexplained after standard genetic testing (such as karyotyping, chromosomal microarray, or whole-exome sequencing). It will also learn how WGS results may affect pregnancy management and family decision-making. The main questions it aims to answer are: How often does WGS identify a genetic cause in these fetuses? Does WGS find more genetic causes compared to standard genetic tests? Can combining WGS with other molecular analyses help discover new disease genes or pathways? Researchers will compare WGS results to results from standard genetic tests to see if WGS finds more genetic causes. Participants are pregnant women whose fetuses have structural abnormalities seen on ultrasound or MRI, with negative results from routine genetic testing. Participants will: Undergo an invasive procedure (such as amniocentesis) or provide postnatal samples as part of their regular medical care Allow the use of leftover samples for WGS and additional molecular studies Be followed until after delivery to collect information on pregnancy outcomes and neonatal health

Conditions

Prenatal Diagnosis; Fetal Diseases

Outcome Measures

Primary Outcomes (3)

• Diagnostic yield of WGS

  Proportion of fetuses with structural malformations or significant ultrasound abnormalities in whom whole-genome sequencing (WGS) using fetal and related tissues identifies at least one pathogenic or likely pathogenic variant. Overall diagnostic yield (including pathogenic/likely pathogenic variants and variants of uncertain significance reclassified as pathogenic/likely pathogenic based on additional evidence) will also be reported.

  8 weeks after enrollment of the last participant

• Comparison of diagnostic increment of WGS vs. standard clinical testing pathway

  Difference in diagnostic rate (proportion of fetuses with pathogenic/likely pathogenic variants) between whole-genome sequencing (WGS) and the current standard clinical testing pathway (karyotyping, CMA/CNV-seq, WES/panel). Stratified analysis by malformation type (e.g., isolated CNS, cardiac, skeletal, multiple systems) and by pattern of system involvement will be reported.

  12 weeks after enrollment of the last participant

• Number of novel candidate disease genes and enriched molecular pathways

  Count of novel candidate disease genes or regulatory elements identified by integrated multi-omics analysis. List of enriched KEGG pathways and GO terms (with FDR \< 0.05) associated with fetal developmental abnormalities.

  At study completion (average 24 months after first participant enrollment)

Secondary Outcomes (4)

• Phenotypic stratification system and gene pathway enrichment results

  At study completion (average 24 months after first participant enrollment)

• Reclassification rate of variants of uncertain significance (VUS) and impact on counseling decisions

  At study completion (average 24 months after first participant enrollment)

• Establishment of a multicenter database and biobank

  At study completion (average 24 months after first participant enrollment)

• Standardized data submission and sharing protocols

  At study completion (average 24 months after first participant enrollment)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Pregnant women aged 18 years or older with singleton pregnancies, whose fetuses have structural abnormalities detected by ultrasound or MRI between 11+0 and 32+0 weeks of gestation, and who are scheduled to undergo invasive or postnatal genetic diagnostic procedures.

You may qualify if:

• Pregnant women aged ≥ 18 years.
• Singleton pregnancy.
• Gestational age between 11+0 and 32+0 weeks, with ultrasound or MRI indicating a definite structural malformation in the fetus (may be with or without soft marker abnormalities) requiring prenatal diagnosis (see Appendices 1 and 2). Fetal developmental abnormalities include those of the central nervous system, cardiovascular system, craniofacial/neck region, chest/mediastinum, abdomen/digestive tract, urinary system, skeletal system/limbs, and systemic abnormalities such as fetal hydrops, abnormally thickened placenta with hydrops, and severe growth restriction. Criteria for ultrasound soft markers and structural malformations are provided in the appendices.
• Planned to undergo at least one invasive or postnatal procedure for genetic diagnosis, and consent to the use of residual diagnostic samples for research testing.
• Signed unified informed consent form, agreement to follow-up, and consent for storage and submission of samples and data according to the protocol.

You may not qualify if:

• Age \< 18 years or individuals lacking full capacity for civil conduct.
• Twin or multiple pregnancies.
• Known parental or familial carrier status of a pathogenic variant highly consistent with the current fetal phenotype, where testing is planned only for targeted confirmation.
• Refusal to consent to the storage and use of samples and data for this study.
• Other conditions deemed unsuitable for participation in this study by the investigator.

Sponsors & Collaborators

• Women's Hospital School Of Medicine Zhejiang University: lead

Study Sites (4)

Women's Hospital School of Medicine Zhejiang University

Hangzhou, Zhejiang, 310006, China

RECRUITING

Huzhou Maternity & Child Care Hospital

Huzhou, Zhejiang, 313000, China

RECRUITING

Quzhou Maternal and Child Health Care Hospital

Quzhou, Zhejiang, 324000, China

RECRUITING

Shaoxing Maternity & Child Care Hospital

Shaoxing, Zhejiang, 312000, China

RECRUITING

MeSH Terms

Conditions

Fetal Diseases

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Central Study Contacts

Qiong Luo

CONTACT

+86 571 89998819; luoq@zju.edu.cn

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 9, 2026
• First Posted: May 26, 2026
• Study Start: March 12, 2026
• Primary Completion (Estimated): September 12, 2027
• Study Completion (Estimated): March 12, 2028
• Last Updated: May 26, 2026

Record last verified: 2026-03

Locations

CN (4)