2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Cell-based Noninvasive Prenatal Screening for a Comprehensive Fetal Genome Profiling for Pathogenic Submicroscopic CNVs in Circulating Trophoblasts from Maternal Blood

Cell-based Noninvasive Prenatal Screening for a Comprehensive Fetal Genome Profiling for Pathogenic Submicroscopic CNVs in Circulating Trophoblasts from Maternal Blood

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Researchers have developed a cell-based noninvasive prenatal screening method for comprehensive fetal genome profiling. The study aimed to detect pathogenic submicroscopic copy number variations (CNVs) in circulating trophoblasts from maternal blood. An automated approach was used to isolate intact circulating extravillous trophoblasts (cEVTs) from maternal blood, and single-cell fetal genome profiling was performed for CNV detection. A total of 372 pregnant women were enrolled in the study.<br /><br />In 61 patient samples, fetal chromosomal microarray analysis (CMA) was performed on invasively obtained fetal material, and the results were compared to the single-cell cEVT analysis result. Two cases were identified with pathogenic CNVs detected by CMA, including a 16p13.11 deletion of 800kb that was detected by single-cell trophoblast analysis using the method. In the population with normal CMA results, six (likely) benign CNVs were identified by single-cell analysis of cEVTs.<br /><br />The study concluded that single-cell cEVT analysis provided full concordance for CNV detection with clinical CMA. The current limit of detection using low-coverage next-generation sequencing (NGS) was determined to be 800kb, allowing for the identification of most known pathogenic CNVs. The study supported the clinical feasibility of an automated workflow for noninvasive comprehensive fetal genome profiling, which could reduce the residual risk for fetal pathogenic genomic abnormalities down to approximately 1Mb in size.<br /><br />Compared to cell-free DNA testing, the noninvasive analysis of pure unfragmented genomic DNA from the conceptus was found to be highly advantageous as it avoids confounding factors related to the maternal genetic make-up and allows for higher resolution in comprehensive fetal genome profiling, including the detection of pathogenic submicroscopic imbalances. The findings suggest the potential of this method for improving prenatal screening and reducing the risk of fetal genetic abnormalities.

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Co-Author - Anna Doffini, PhD; Co-Author - Claudio Forcato, PhD; Co-Author - Chiara Mangano, PhD; Co-Author - Debora Lattuada, PhD; Co-Author - Roberta Aversa, M.Sc; Co-Author - Chiara Maranta, M.Sc; Co-Author - Emilia D. Giovannone, PhD; Co-Author - Genny Buson, PhD; Co-Author - Chiara Bolognesi, M.Sc; Co-Author - Rebecca Maiocchi, PhD; Co-Author - Martina Dori, PhD; Co-Author - Liyana Jamal, M.Sc; Co-Author - Raidah B. Ahmad, M.Sc; Co-Author - George S.H. Yeo, MD; Co-Author - Tai Wai Yeo, PhD; Co-Author - Silvia Saragozza, PhD; Co-Author - Rosamaria Silipigni, PhD; Co-Author - Marta Serafini, PhD; Co-Author - Andrea Biondi, MD; Co-Author - Sofia Perego, M.Sc; Co-Author - Patrizia Vergani, MD; Co-Author - Enrico Ferrazzi, MD; Co-Author - Paola Ricciardi-Castagnoli, PhD; Co-Author - Thomas J. Musci, MD; Presenting Author - Francesca Romana Grati, MSCs, PhD, CLG;

Meta Tag

Cell free DNA/cfDNA

Chromosomal Abnormalities

Microarray

NextGen Sequencing

Noninvasive prenatal screening (NIPS)

Prenatal Diagnosis

Co-Author Anna Doffini, PhD

Co-Author Claudio Forcato, PhD

Co-Author Chiara Mangano, PhD

Co-Author Debora Lattuada, PhD

Co-Author Roberta Aversa, M.Sc

Co-Author Chiara Maranta, M.Sc

Co-Author Emilia D. Giovannone, PhD

Co-Author Genny Buson, PhD

Co-Author Chiara Bolognesi, M.Sc

Co-Author Rebecca Maiocchi, PhD

Co-Author Martina Dori, PhD

Co-Author Liyana Jamal, M.Sc

Co-Author Raidah B. Ahmad, M.Sc

Co-Author George S.H. Yeo, MD

Co-Author Tai Wai Yeo, PhD

Co-Author Silvia Saragozza, PhD

Co-Author Rosamaria Silipigni, PhD

Co-Author Marta Serafini, PhD

Co-Author Andrea Biondi, MD

Co-Author Sofia Perego, M.Sc

Co-Author Patrizia Vergani, MD

Co-Author Enrico Ferrazzi, MD

Co-Author Paola Ricciardi-Castagnoli, PhD

Co-Author Thomas J. Musci, MD

Presenting Author Francesca Romana Grati, MSCs, PhD, CLG

Keywords

noninvasive prenatal screening

fetal genome profiling

copy number variations

circulating trophoblasts

maternal blood

automated approach

single-cell analysis

chromosomal microarray analysis

pathogenic CNVs

low-coverage next-generation sequencing