Prenatal Cell-free DNA Screening in Pregnancies With Diverse Genetic Risk Profiles Utilizing Targeted and Whole-exome Sequencing
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 1,600
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
This prospective, multicenter clinical study is designed to evaluate the clinical validity and utility of a novel non-invasive prenatal screening platform, COATE-seq (Coordinative Allele-Aware Target Enrichment Sequencing). The study assesses the performance of cfDNA-based testing that integrates both targeted panel and whole-exome sequencing (WES) approaches to detect a broad range of fetal genetic abnormalities-including aneuploidies, microdeletions, monogenic pathogenic variants, uniparental disomy (UPD), and hydatidiform moles from a single maternal blood sample. The overarching aim is to establish the diagnostic accuracy, clinical effectiveness, and real-world impact of this comprehensive assay in routine prenatal care settings.
The primary objective is to evaluate test performance through standard metrics including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), benchmarked against confirmatory diagnostic results. The secondary objectives focus on comparing detection rates across genetic risk subgroups (e.g., structural anomalies on ultrasound), quantifying the incremental yield of WES over targeted panels, and assessing clinical impact on management decisions. These endpoints are particularly relevant in an era of expanding therapeutic options for genetic conditions where early, non-invasive detection may significantly influence prenatal or perinatal interventions.
Participants will be pregnant women between 9+0 and 25+6 weeks of gestation with singleton pregnancies who meet the following inclusion criteria:
Age 18 years or older;
Willingness to provide informed consent and participate in all study procedures;
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
结局指标
主要结局
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.
时间窗: 18 months
次要结局
- Assess efficacy across diverse genetic risk populations by analyzing detection rates of pathogenic variants associated with fetal indications.(8 months)