Utility of Whole Genome Sequencing in Fetuses With Abnormal Ultrasound Findings

Women's Hospital School Of Medicine Zhejiang University1,000 enrolled

Overview

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 Type

OBSERVATIONAL

Enrollment

1,000

Conditions

Prenatal Diagnosis Fetal Diseases

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.