Utility of Whole Genome Sequencing in Fetuses With Abnormal Ultrasound Findings

Condition(s) studied

Study 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

Eligibility

Primary outcome measure(s)

• Diagnostic yield of WGS — 8 weeks after enrollment of the last participant
  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.
• Comparison of diagnostic increment of WGS vs. standard clinical testing pathway — 12 weeks after enrollment of the last participant
  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.
• Number of novel candidate disease genes and enriched molecular pathways — At study completion (average 24 months after first participant enrollment)
  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.

Trial sites (4)

More Women's Hospital School Of Medicine Zhejiang University trials in China