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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
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| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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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.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Qiong Luo | Contact | +86 571 89998819 | luoq@zju.edu.cn |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Women's Hospital School of Medicine Zhejiang University | Recruiting | Hangzhou | Zhejiang | 310006 | China |
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| ID | Term |
|---|---|
| D005315 | Fetal Diseases |
| ID | Term |
|---|---|
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| 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) |
| Huzhou Maternity & Child Care Hospital | Recruiting | Huzhou | Zhejiang | 313000 | China |
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| Quzhou Maternal and Child Health Care Hospital | Recruiting | Quzhou | Zhejiang | 324000 | China |
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| Shaoxing Maternity & Child Care Hospital | Recruiting | Shaoxing | Zhejiang | 312000 | China |
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