Fetal Diseases, Prenatal Diagnosis
Conditions
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
Interventions
None listed
Sponsors
Women's Hospital School Of Medicine Zhejiang University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phenotypic stratification system and gene pathway enrichment results | At study completion (average 24 months after first participant enrollment) | 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. |
| Reclassification rate of variants of uncertain significance (VUS) and impact on counseling decisions | At study completion (average 24 months after first participant enrollment) | 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. |
| Establishment of a multicenter database and biobank | At study completion (average 24 months after first participant enrollment) | 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. |
| Standardized data submission and sharing protocols | At study completion (average 24 months after first participant enrollment) | 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. |
Countries
China
Contacts
CONTACTQiong Luo
Outcome results
None listed