Utility of Whole Genome Sequencing in Fetuses With Abnormal Ultrasound Findings

Clinical Study on Prenatal Diagnosis of Fetal Abnormalities of Unknown Cause Using Whole-Genome Sequencing: A Multicenter Study

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

Study Overview

• Status: Recruiting
• Conditions: Fetal Diseases; Prenatal Diagnosis

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

• Study Contact: Name: Qiong Luo; Phone Number: +86 571 89998819; Email: luoq@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310006
      • Recruiting
      • Women's Hospital School of Medicine Zhejiang University
      • Contact: Qiong Luo; Phone Number: +86 571 89998819; Email: luoq@zju.edu.cn
    • Huzhou, Zhejiang, China, 313000
      • Recruiting
      • Huzhou Maternity & Child Care Hospital
      • Contact: Liping Qiu; Phone Number: +86 15906823270; Email: 392686340@qq.com
    • Quzhou, Zhejiang, China, 324000
      • Recruiting
      • Quzhou Maternal and Child Health Care Hospital
      • Contact: Yuying Zhu; Phone Number: +86 15257023995; Email: zhuyuy123@163.com
    • Shaoxing, Zhejiang, China, 312000
      • Recruiting
      • Shaoxing Maternity & Child Care Hospital
      • Contact: Hualin Xu; Phone Number: +86 13867526767; Email: xhl0175@sina.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• 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.

Description

Inclusion Criteria:

1. Pregnant women aged ≥ 18 years.
2. Singleton pregnancy.
3. 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.
4. 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.
5. Signed unified informed consent form, agreement to follow-up, and consent for storage and submission of samples and data according to the protocol.

Exclusion Criteria:

1. Age < 18 years or individuals lacking full capacity for civil conduct.
2. Twin or multiple pregnancies.
3. 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.
4. Refusal to consent to the storage and use of samples and data for this study.
5. Other conditions deemed unsuitable for participation in this study by the investigator.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phenotypic stratification system and gene pathway enrichment results	Phenotypic classification system (based on organ/system involvement: isolated, multiple, syndromic). For each subtype: (1) count and frequency of pathogenic/likely pathogenic variants; (2) count of variant types (SNV, Indel, SV, CNV); (3) list of enriched KEGG pathways and GO terms with FDR < 0.05.	At study completion (average 24 months after first participant enrollment)
Reclassification rate of variants of uncertain significance (VUS) and impact on counseling decisions	Proportion of VUS reclassified to pathogenic/likely pathogenic or benign/likely benign after multi-omics integration. Number of participants/families with altered genetic counseling or clinical decision-making (e.g., termination, prenatal intervention, postnatal follow-up plan) due to reclassification.	At study completion (average 24 months after first participant enrollment)
Establishment of a multicenter database and biobank	A unified, relational database containing de-identified clinical phenotypes, genotypes (WGS variants), multi-omics data (e.g., transcriptomic, epigenomic), and biospecimen inventory (e.g., DNA, RNA, plasma, tissue blocks) from participating centers. Database completion will be defined as ≥90% of expected participants with all required data types uploaded and quality-controlled. Biobank completion will be defined as ≥90% of expected biospecimens collected, processed, and stored with traceable metadata.	At study completion (average 24 months after first participant enrollment)
Standardized data submission and sharing protocols	Completion of a written protocol document (yes/no) covering sample submission, data formats, quality thresholds, reporting template (ACMG/AMP classification), clinical data dictionary, and de-identification rules, with sign-off obtained from all participating centers' principal investigators and data managers.	At study completion (average 24 months after first participant enrollment)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2026
• Primary Completion (Estimated): September 12, 2027
• Study Completion (Estimated): March 12, 2028

Study Registration Dates

• First Submitted: April 9, 2026
• First Submitted That Met QC Criteria: May 20, 2026
• First Posted (Actual): May 26, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Fetal Diseases
• Other Study ID Numbers: IRB-20260095-R