Prenatal Cell-free DNA Screening in Pregnancies With Diverse Genetic Risk Profiles Utilizing Targeted and Whole-exome Sequencing
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Enrollment
- 1,600
- Locations
- 2
- Primary Endpoint
- Determine the clinical validity of targeted and whole exome cfDNA analyses, assessed through sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) relative to diagnostic standards.
Study Overview
Brief Summary
This multicenter study aims to recruit a minimum of 1,600 pregnant women, encompassing individuals with varying levels of genetic risk. The study particularly focuses on cases with increased fetal nuchal translucency (NT ≥3.5 mm), additional ultrasound markers, and/or fetal structural anomalies. Peripheral blood samples of eligible participants will be collected for two state-of-the-art cfDNA tests based on coordinative allele-aware target enrichment sequencing (COATE-seq): (1) a targeted panel to screen for frequent chromosomal aneuploidies, microdeletions/duplications, and dominant single-gene conditions, and (2) comprehensive whole-exome cfDNA sequencing for aneuploidies, microdeletions/duplications, monogenic variants (both dominant and recessive variants), uniparental disomy, and hydatidiform moles. The results of both cfDNA tests will be compared with those from invasive or postnatal diagnostic testing. Pregnancy outcome will be followed up to six weeks postpartum. The primary goal is to determine the clinical validity of targeted and whole exome cfDNA analyses, assessed through sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) relative to diagnostic standards. Secondary goal is to assess efficacy across diverse genetic risk populations by analyzing detection rates of pathogenic variants associated with fetal indications. The clinical utility of cfDNA screening will also be evaluated by its impact on clinical management decisions, including follow-up diagnostic procedures or prenatal/perinatal interventions.
Detailed Description
This is a prospective, multicenter clinical study evaluating the clinical validity and utility of a next-generation non-invasive prenatal screening platform, COATE-seq (Coordinative Allele-Aware Target Enrichment Sequencing). COATE-seq is a cfDNA-based approach that integrates hybrid capture panel sequencing with whole-exome sequencing (WES) from a single maternal plasma sample, enabling detection of a broad spectrum of fetal genetic conditions. These include common and rare aneuploidies, clinically significant microdeletions, monogenic pathogenic variants, uniparental disomy (UPD), and molar pregnancies.
The platform leverages coordinated allelic modeling and deep sequencing to enhance sensitivity for low-allelic-fraction variants, including those in autosomal recessive and dominant genes. The panel-based component targets 56 monogenic conditions selected using the SEPH framework (Severe, Early-onset, Prevalent, High detectability), while the WES component interrogates approximately 19,000 protein-coding genes to enable secondary and exploratory analyses of ultra-rare or novel variants. Variant interpretation adheres to ACMG/AMP guidelines, and only pathogenic or likely pathogenic variants associated with severe outcomes are reported.
The study is designed to benchmark the performance of this integrated assay against conventional diagnostic standards, including karyotyping, chromosomal microarray (CMA), targeted gene sequencing, whole-exome sequencing, and whole-genome sequencing. Reference testing is performed prenatally or postnatally, and in select cases, UPD is confirmed via methylation-specific PCR or short tandem repeat (STR) analysis.
Data collected across the study include:
Clinical history and prenatal imaging findings
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Adult pregnant woman (≥18 years old)
- •Gestational age between 9+0 and 25+6 weeks
- •Singleton pregnancy
- •Pregnancy with indications for prenatal diagnosis due to:
- •Increased nuchal translucency (NT) ≥3.5 mm: capped at 25% of total subjects
- •Increased NT ≥3.5 mm AND presence of any other "soft marker" or structural anomaly: capped at 25% of total subjects
- •Presence of structural anomaly: at least 50% of total subjects
- •Agree to participate in the clinical study for being followed-up and accept at least one molecular diagnosis (diagnostic procedures performed on prenatal invasive specimens, product of conception, umbilical cord blood, or other specimens) and possible family member testing
Exclusion Criteria
- •Age under 18 years
- •Gestational age is less than 9+0 weeks or greater than 25+6 weeks
- •One parent or other family member has a known pathogenic variant linked to the fetal ultrasound finding(s)
- •Conditions affecting the accuracy of cfDNA assay (e.g., maternal malignancy during pregnancy, maternal allogeneic blood transfusion, organ transplantation, or cell therapy within the past year)
Outcomes
Primary Outcomes
Determine the clinical validity of targeted and whole exome cfDNA analyses, assessed through sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) relative to diagnostic standards.
Time Frame: 18 months
Determine the clinical validity of targeted and whole exome cfDNA analyses, assessed through sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) relative to diagnostic standards.
Time Frame: 18 months
Secondary Outcomes
- Assess efficacy across diverse genetic risk populations by analyzing detection rates of pathogenic variants associated with fetal indications.(8 months)
- Assess efficacy across diverse genetic risk populations by analyzing detection rates of pathogenic variants associated with fetal indications.(8 months)